Chemokine receptor antagonists and methods of use therefor

ABSTRACT

Disclosed are novel compounds and a method of treating a disease associated with aberrant leukocyte recruitment and/or activation. The method comprises administering to a subject in need an effective amount of a compound represented by:  
                 
 
     and physiologically acceptable salts thereof.

RELATED APPLICATIONS

[0001] This application is a continuation of U.S. application Ser. No.09/362,837, filed Jul. 28, 1999, which is a continuation-in-part of U.S.application Ser. No. 09/235,102 (U.S. Pat. No. 6,329,385 B1), filed Jan.21, 1999, which is a continuation-in-part of U.S. application Ser. No.09/148,823, filed Sep. 4, 1998, which is a continuation-in-part of U.S.application Ser. No. 09/010,320, filed Jan. 21, 1998, now abandoned; theentire teachings of all above-referenced applications are incorporatedherein by reference.

BACKGROUND OF THE INVENTION

[0002] Chemoattractant cytokines or chemokines are a family ofproinflammatory mediators that promote recruitment and activation ofmultiple lineages of leukocytes and lymphocytes. They can be released bymany kinds of tissue cells after activation. Continuous release ofchemokines at sites of inflammation mediates the ongoing migration ofeffector cells in chronic inflammation. The chemokines characterized todate are related in primary structure. They share four conservedcysteines, which form disulfide bonds. Based upon this conservedcysteine motif, the family is divided into two main branches, designatedas the C—X—C chemokines (α-chemokines), and the C—C chemokines(β-chemokines), in which the first two conserved cysteines are separatedby an intervening residue, or adjacent respectively (Baggiolini, M. andDahinden, C. A., Immunology Today, 15:127-133 (1994)).

[0003] The C—X—C chemokines include a number of potent chemoattractantsand activators of neutrophils, such as interleukin 8 (IL-8), PF4 andneutrophil-activating peptide-2 (NAP-2). The C—C chemokines includeRANTES (Regulated on Activation, Normal T Expressed and Secreted), themacrophage inflammatory proteins 1α and 1 β (MIP-1α and MIP-1β), eotaxinand human monocyte chemotactic proteins 1-3 (MCP-1, MCP-2, MCP-3), whichhave been characterized as chemoattractants and activators of monocytesor lymphocytes but do not appear to be chemoattractants for neutrophils.Chemokines, such as RANTES and MIP-1α, have been implicated in a widerange of human acute and chronic inflammatory diseases includingrespiratory diseases, such as asthma and allergic disorders.

[0004] The chemokine receptors are members of a superfamily of Gprotein-coupled receptors (GPCR) which share structural features thatreflect a common mechanism of action of signal transduction (Gerard, C.and Gerard, N. P., Annu Rev. Immunol., 12:775-808 (1994); Gerard, C. andGerard, N. P., Curr. Opin. Immunol., 6:140-145 (1994)). Conservedfeatures include seven hydrophobic domains spanning the plasma membrane,which are connected by hydrophilic extracellular and intracellularloops. The majority of the primary sequence homology occurs in thehydrophobic transmembrane regions with the hydrophilic regions beingmore diverse. The first receptor for the C—C chemokines that was clonedand expressed binds the chemokines MIP-1α and RANTES. Accordingly, thisMIP-1α/RANTES receptor was designated C—C chemokine receptor 1 (alsoreferred to as CCR-1; Neote, K., et al., Cell, 72:415-425 (1993); Horuk,R. et al., WO 94/11504, May 26, 1994; Gao, J. -I. et al., J. Exp. Med.,1 77:1421-1427 (1993)). Three receptors have been characterized whichbind and/or signal in response to RANTES: CCR3 mediates binding andsignaling of chemokines including eotaxin, RANTES, and MCP-3 (Ponath etal., J. Exp. Med., 183:2437 (1996)), CCR4 binds chemokines includingRANTES, MIP-1α, and MCP-1 (Power, et al., J. Biol. Chem., 270:19495(1995)), and CCR5 binds chemokines including MIP-1α, RANTES, and MIP-1β(Samson, et al., Biochem. 35: 3362-3367 (1996)). RANTES is a chemotacticchemokine for a variety of cell types, including monocytes, eosinophils,and a subset of T-cells. The responses of these different cells may notall be mediated by the same receptor, and it is possible that thereceptors CCR1, CCR4 and CCR5 will show some selectivity in receptordistribution and function between leukocyte types, as has already beenshown for CCR3 (Ponath et al.). In particular, the ability of RANTES toinduce the directed migration of monocytes and a memory population ofcirculating T-cells (Schall, T. et al., Nature, 347:669-71 (1990))suggests this chemokine and its receptor(s) may play a critical role inchronic inflammatory diseases, since these diseases are characterized bydestructive infiltrates of T cells and monocytes.

[0005] Many existing drugs have been developed as antagonists of thereceptors for biogenic amines, for example, as antagonists of thedopamine and histamine receptors. No successful antagonists have yetbeen developed to the receptors for the larger proteins such aschemokines and C5a. Small molecule antagonists of the interactionbetween C—C chemokine receptors and their ligands, including RANTES andMIP-1α, would provide compounds useful for inhibiting harmfulinflammatory processes “triggered” by receptor ligand interaction, aswell as valuable tools for the investigation of receptor-ligandinteractions.

SUMMARY OF THE INVENTION

[0006] It has now been found that a class of small organic molecules areantagonists of chemokine receptor function and can inhibit leukocyteactivation and/or recruitment. An antagonist of chemokine receptorfunction is a molecule which can inhibit the binding and/or activationof one or more chemokines, including C—C chemokines such as RANTES,MIP-1α, MCP-2, MCP-3 and MCP-4 to one or more chemokine receptors onleukocytes and/or other cell types. As a consequence, processes andcellular responses mediated by chemokine receptors can be inhibited withthese small organic molecules. Based on this discovery, a method oftreating a disease associated with aberrant leukocyte recruitment and/oractivation is disclosed as well as a method of treating a diseasemediated by chemokine receptor function. The method comprisesadministering to a subject in need an effective amount of a compound orsmall organic molecule which is an antagonist of chemokine receptorfunction. Compounds or small organic molecules which have beenidentified as antagonists of chemokine receptor function are discussedin detail hereinbelow, and can be used for the manufacture of amedicament for treating or for preventing a disease associated withaberrant leukocyte recruitment and/or activation. The invention alsorelates to the disclosed compounds and small organic molecules for usein treating or preventing a disease associated with aberrant leukocyterecruitment and/or activation. The invention also includespharmaceutical compositions comprising one or more of the compounds orsmall organic molecules which have been identified herein as antagonistsof chemokine function and a suitable pharmaceutical carrier. Theinvention further relates to novel compounds which can be used to treatan individual with a disease associated with aberrant leukocyterecruitment and/or activation and methods for their preparation.

BRIEF DESCRIPTION OF THE DRAWINGS

[0007]FIG. 1 is a schematic showing the preparation of the compoundsrepresented by Structural Formula (I).

[0008]FIG. 2 is a schematic showing the preparation of the compoundsrepresented by Compound (VI-b).

[0009]FIG. 3 is a schematic showing the preparation of the compoundsrepresented by Structural Formula (I)

[0010]FIG. 4 is a schematic showing the preparation of the compoundsrepresented by Structural Formula (I), wherein Z is represented byStructural Formula (III) and wherein Ring A and/or Ring B in Z issubstituted with R⁴⁰.

[0011]FIG. 5 is a schematic showing the preparation of the compoundsrepresented by Structural Formula (I), wherein Z is represented byStructural Formula (III) and wherein Ring A and/or Ring B in Z issubstituted with —(O)_(u)—(CH₂)_(t)—COOR²⁰, —(O)_(u)—(CH₂)_(t)—OC(O)R²⁰,—(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)O—R²⁰.

[0012] FIGS. 6A-6Z show the structures of exemplary compounds of thepresent invention.

[0013]FIG. 7 shows the preparation of compounds represented byStructural Formula (I), where in Z is represented by Structural Formulas(III) and wherein Ring A or Ring B in Z is substituted with R⁴⁰.

[0014]FIG. 8A is a schematic showing the preparation of4-(4-chlorophenyl)-4-fluoropiperidine.

[0015]FIG. 8B is a schematic showing the preparation of4-4-azido-4-(4-chlorophenyl)piperidine.

[0016]FIG. 8C is a schematic showing the preparation of4-(4-chlorophenyl)-4-methylpiperidine.

[0017]FIG. 9A is a schematic showing the preparation of compoundsrepresented by Structural Formulas (I), (VIII) and (VIII) wherein R¹ isan amine.

[0018]FIG. 9B is a schematic showing the preparation of compoundsrepresented by Structural Formulas (I), (VIII) and (VIII) wherein R¹ isan alkylamine.

[0019]FIG. 9C is a schematic showing the preparation of2-(4-chlorophenyl)-1-(N-methyl)ethylamine.

[0020]FIG. 9D is a schematic showing the preparation of3-(4-chlorophenyl)-3-chloro-1-hydroxypropane.

[0021]FIG. 9E is a schematic showing the preparation of3-(4-chlorophenyl)-1-N-methylaminopropane.

[0022]FIG. 10A is a schematic showing the preparation of3-(4-chlorophenyl)-3-hydroxyl-3-methyl-1-N-methylaminopropane.

[0023]FIG. 10B is a schematic showing the preparation of1-(4-chlorobenzoyl)-1,3-propylenediamine.

[0024]FIG. 10C is a schematic showing three procedures for thepreparation of compounds represented by Structural Formulas (I),(VII),(VIII), (IX) and (XI) wherein Z is represented by Structural Formula(III) and wherein Ring A or Ring B in Z is substituted with R⁴⁰ In FIG.10C., R⁴⁰ is represented by —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²², U is one, tis zero.

[0025]FIG. 10D is a schematic showing the preparation of4-(4-chlorophenyl)-4-pyridine.

[0026] FIGS. 11A-11K show the structures of exemplary compounds of thepresent invention.

DETAILED DESCRIPTION OF THE INVENTION

[0027] The present invention relates to small molecule compounds whichare modulators of chemokine receptor function. In a preferredembodiment, the small molecule compounds are antagonists of chemokinereceptor function. Accordingly, processes or cellular responses mediatedby the binding of a chemokine to a receptor can be inhibited (reduced orprevented, in whole or in part), including leukocyte migration, integrinactivation, transient increases in the concentration of intracellularfree calcium [Ca⁺⁺]₁, and/or granule release of proinflammatorymediators.

[0028] The invention further relates to a method of treatment, includingprophylactic and therapeutic treatments, of a disease associated withaberrant leukocyte recruitment and/or activation or mediated bychemokines or chemokine receptor function, including chronicinflammatory disorders characterized by the presence of RANTES, MIP-1α,MCP-2, MCP-3 and/or MCP-4 responsive T cells, monocytes and/oreosinophils, including but not limited to diseases such as arthritis(e.g., rheumatoid arthritis), atherosclerosis, arteriosclerosis,restenosis, ischemia/reperfusion injury, diabetes mellitus (e.g., type 1diabetes mellitus), psoriasis, multiple sclerosis, inflammatory boweldiseases such as ulcerative colitis and Crohn's disease, rejection oftransplanted organs and tissues (i.e., acute allograft rejection,chronic allograft rejection), graft versus host disease, as well asallergies and asthma. Other diseases associated with aberrant leukocyterecruitment and/or activation which can be treated (includingprophylactic treatments) with the methods disclosed herein areinflammatory diseases associated with Human Immunodeficiency Virus (HIV)infection, e.g., AIDS associated encephalitis, AIDS relatedmaculopapular skin eruption, AIDS related interstitial pneumonia, AIDSrelated enteropathy, AIDS related periportal hepatic inflammation andAIDS related glomerulo nephritis. The method comprises administering tothe subject in need of treatment an effective amount of a compound(i.e., one or more compounds) which inhibits chemokine receptorfunction, inhibits the binding of a chemokine to leukocytes and/or othercell types, and/or which inhibits leukocyte migration to, and/oractivation at, sites of inflammation.

[0029] The invention further relates to methods of antagonizing achemokine receptor, such as CCR1, in a mammal comprising administeringto the mammal a compound as described herein.

[0030] According to the method, chemokine-mediated chemotaxis and/oractivation of pro-inflammatory cells bearing receptors for chemokinescan be inhibited. As used herein, “pro-inflammatory cells” includes butis not limited to leukocytes, since chemokine receptors can be expressedon other cell types, such as neurons and epithelial cells.

[0031] While not wishing to be bound by any particular theory ormechanism, it is believed that compounds of the invention areantagonists of the chemokine receptor CCR1, and that therapeuticbenefits derived from the method of the invention are the result ofantagonism of CCR1 function. Thus, the method and compounds of theinvention can be used to treat a medical condition involving cells whichexpress CCR1 on their surface and which respond to signals transducedthrough CCR1, as well as the specific conditions recited above.

[0032] In one embodiment, the antagonist of chemokine receptor functionis represented by Structural Formula (I):

[0033] and physiologically acceptable salts thereof.

[0034] Z is a cycloalkyl or non-aromatic heterocyclic ring group fusedto one, two or more aromatic rings, wherein each ring in Z isindependently substituted or unsubstituted.

[0035] n is an integer, such as an integer from one to about four.Preferably, n is one, two or three. More preferably n is two. Inalternative embodiments, other aliphatic or aromatic spacer groups (L)can be employed for (CH₂)_(n).

[0036] M is >NR² or >CR¹R². M is preferably >C(OH)R².

[0037] R¹ is —H, —OH, —N₃, a halogen, an aliphatic group, a substitutedaliphatic group, an aminoalkyl group, —O-(aliphatic group),—O-(substituted aliphatic group), —SH, —S-(aliphatic group),—S-(substituted aliphatic group), —OC(O)-(aliphatic group),—O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group),—C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR³R⁴, —NR³R⁴; orR¹ can be a covalent bond between the ring atom at M and an adjacentcarbon atom in the ring which contains M. R¹ is preferably —H or —OH.

[0038] R² is —H, —OH, an acyl group, a substituted acyl group, —NR⁵R⁶,an aliphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group, a benzyl group, a substituted benzyl group,a non-aromatic heterocyclic group, a substituted non-aromaticheterocyclic group, —O-(substituted or unsubstituted aromatic group) or—O-(substituted or unsubstituted aliphatic group). R² is preferably anaromatic group or a substituted aromatic group.

[0039] R³, R⁴, R⁵ and R⁶ are independently —H, an acyl group, asubstituted acyl group, an aliphatic group, a substituted aliphaticgroup, an aromatic group, a substituted aromatic group, a benzyl group,a substituted benzyl group, a non-aromatic heterocyclic group or asubstituted non-aromatic heterocyclic group.

[0040] R¹ and R², R³ and R⁴, or R⁵ and R⁶ taken together with the atomto which they are bonded, can alternatively form a substituted orunsubstituted non-aromatic carbocyclic or heterocyclic ring.

[0041] In embodiments where M is >CR¹R² and R¹ is a covalent bondbetween the carbon atom at M and an adjacent carbon atom in the ringwhich contains M, the antagonist of chemokine function can berepresented by Structural Formula (Ia).

[0042] Z, n and R² are as described in Structural Formula (I).

[0043] In one preferred embodiment, Z is a tricyclic ring systemcomprising two carbocyclic aromatic groups fused to a five, six, sevenor eight membered cycloalkyl group or to a non-aromatic heterocyclicring. In one example, Z is represented by Structural Formula (II):

[0044] The phenyl rings in Structural Formula (II), labeled with an “A”and “B”, are referred to herein as “Ring A” and “Ring B”, respectively.The central ring, labeled with a “C”, is referred to as “Ring C” and canbe, for example, a five, six, seven or eight membered non-aromaticcarbocyclic ring (e.g., a cycloheptane or cyclooctane ring) or anon-aromatic heterocyclic ring. When Ring C is a non-aromaticheterocyclic ring, it can contain one or two heteroatoms such asnitrogen, sulfur or oxygen. In particular embodiments, Ring c is When Zis represented by Structural Formula (II), the tricyclic ring system canbe connected to the remainder of the molecule by a covalent double bondbetween a carbon atom in Ring C and the carbon atom which, as depictedin Structural Formula (I), is bonded to Z.

[0045] Ring A and/or Ring B in Structural Formula (II) can beunsubstituted. Alternatively, Ring A and/or Ring B can have one or moresubstituents. Suitable substituents are as described hereinbelow. In oneexample, Ring A or Ring B is substituted with—(O)_(u)—(CH₂)_(t)—C(O)OR²⁰, —(O)_(u)—(CH₂)_(t)—OC(O)R²⁰,—(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)O—R²⁰.

[0046] u is zero or one.

[0047] t is an integer, such as an integer from zero to about three, andthe methylene group —(CH₂)_(t)— can be substituted, as described hereinfor aliphatic groups, or unsubstituted.

[0048] R²⁰, R²¹ or R²² are independently —H, an aliphatic group, asubstituted aliphatic group, an aromatic group, a substituted aromaticgroup or a non-aromatic heterocyclic group. Alternatively, R²¹ and R²²,taken together with the nitrogen atom to which they are bonded, can forma non-aromatic heterocyclic ring.

[0049] Ring C optionally contains one or more substituents, as describedhereinbelow.

[0050] Examples of suitable tricyclic ring systems, Z, are provided byStructural Formula (III):

[0051] Ring A and Ring B in Structural Formula (III) are as describedfor Structural Formula (II).

[0052] X₁ is a bond, —O—, —S—, —CH₂—, —CH₂—CH₂—, —CH₂—S—, —S—CH₂—,—O—CH₂—, —CH₂—O—, —NR_(c)—CH₂—, —CH₂—NR_(c)—, —SO—CH₂—, —CH₂—SO—,—S(O)₂—CH₂—, —CH₂—S(O)₂—, —CH═CH—, —NRC—CO— or —CO—NRC—. Preferably X,is —CH₂—O—, —CH₂—CH₂—, —CH₂—S—, —Nr_(c)—CO— or —CO—NR_(c)—.

[0053] R_(c) is hydrogen, an aliphatic group, a substituted aliphaticgroup, an aromatic group, a substituted aromatic group, a benzyl groupor a substituted benzyl group.

[0054] In one example, R_(c) is —(CH₂)_(s)—COOR³⁰,—(CH₂)_(s)—C(O)—NR³¹R³² or —(CH₂)_(s)—NHC(O)—O—R³⁰, wherein s is aninteger, such as an integer from one to about three;

[0055] R³⁰, R³¹ and R³² are independently —H, an aliphatic group, asubstituted aliphatic group, an aromatic group, a substituted aromaticgroup or a non-aromatic heterocyclic group. Alternatively, R³¹ and R³²,taken together with the nitrogen atom to which they are bonded, form anon-aromatic heterocyclic ring.

[0056] Other examples of suitable tricyclic ring systems for Z includebenzodiazepines, benzooxazepines, benzooxazines, phenothiazines andgroups represented by the following structural formulas:

[0057] In another preferred embodiment, Z is a tricyclic ring systemcomprising two aromatic groups fused to a seven or eight memberedcycloalkyl group or to a non-aromatic heterocyclic ring, wherein atleast one of the aromatic groups is a heteroaryl group. In one example,Z is represented by Structural Formula (IV):

[0058] Ring A in Structural Formula (IV) can be a substituted orunsubstituted heteroaryl group. Ring B in Structural Formula (IV) can bea substituted or unsubstituted aromatic group, e.g., a heteroaryl groupor carbocyclic aryl group. Suitable substituents are as describedhereinbelow. In one example, Ring A and/or Ring B is substituted with—(O)_(u)—(CH₂)_(t)—C(O)OR²⁰, —(O)_(u)—(CH₂)_(t)—OC(O)R²⁰,—(O)_(u)—(CH₂)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)O—R²⁰ asdescribed above. u, t, R²⁰, R²¹, and R²² are as described above. X₁ andR_(c) can be as described above for Structural Formula (III).

[0059] In another embodiment of the present invention Z is representedby Structural Formula (IV), wherein Ring A is a pyridyl group and Ring Bis an aromatic or heteroaromatic group. In one example, Z is representedby Structural Formula (IVa):

[0060] In this embodiment Ring A and Ring B are independentlysubstituted or unsubstituted, and Ring B is preferably a phenyl group.X₁ and R_(c) can be as described above for Structural Formula (III).

[0061] In another embodiment, both Ring A and Ring B are pyridyl groups,and Z is represented by Structural Formula (IVb):

[0062] Ring A and Ring B can be independently substituted orunsubstituted as described above in Structural Formula (II), and X₁ canbe as described above for Structural Formula (III).

[0063] In another embodiment of the present invention Z is representedby Structural Formula (V):

[0064] Ring A and Ring B can be independently substituted orunsubstituted as described above in Structural Formula (II), and X₁ canbe as described above for Structural Formula (III).

[0065] In a preferred embodiment, Ring B in Structural Formula (V) issubstituted para to the carbon atom of Ring B which is bonded to X₁ ofRing C, and Z is represented by Structural Formula (VI):

[0066] X₁ can be as described above in Structural Formula (II).Preferably X, is —CH₂—O—, —CH₂—CH₂— or —CH₂—S—.

[0067] R⁴⁰ is a substituent as described hereinbelow for aromaticgroups. In one embodiment, R⁴⁰ is —OH, —COOH, a halogen, —NO₂, analiphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group, —NR²⁴R²⁵, —CONR²⁴R²⁵, —Q-(aliphatic group),—Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substitutedaliphatic group), —O-(aromatic group), —O-(substituted aromatic group),an electron withdrawing group, —(O)_(u)—(CH₂), —C(O)OR², —(O)_(u)—(CH₂),—OC(O)R²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR², R²² or—(O)_(u)—(CH₂)_(t)—NHC(O)O—R²⁰. Q, R²⁰, R²¹, R²², R²⁴, R²⁵ u and t areas described herein.

[0068] Preferably R⁴⁰ is an aliphatic group, substituted aliphaticgroup, —O-(aliphatic group) or —O-(substituted aliphatic group). Morepreferably R⁴⁰ is an —O-alkyl, such as —O—CH₃, —O—C₂H₅, —O—C₃H₇ or—O—C₄H₉.

[0069] In another embodiment, R⁴⁰ can be represented by —(O)_(u)—(CH₂)—C(O)—NR²¹R²², wherein u is one, t is zero, and R²¹ and R²² are asdescribed herein. In this embodiment, R²¹ and R²² can each independentlybe —H, a substituted or unsubstituted aliphatic group, a substituted orunsubstituted aromatic group, or R²¹ and R²² taken together with thenitrogen atom to which they are bonded form a nonaromatic heterocyclicring (e.g., pyrrolidine, piperidine, morpholine).

[0070] In another embodiment, R⁴⁰ can be represented by—(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²², wherein u is zero, t is one to aboutthree, and R²¹ and R²² are as described herein.

[0071] In another embodiment, R⁴⁰ can be represented by—(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²², wherein both u and t are zero, and R²¹and R²² are as described herein.

[0072] In another embodiment, R⁴⁰ is an aliphatic group (e.g., methyl,ethyl, propyl) that is substituted with —NR²⁴R²⁵ or —CONR²⁴R²⁵, whereinR²⁴ and R²⁵ are as described herein. For example, R⁴⁰ can be representedby

[0073] In a preferred embodiment, the chemokine receptor antagonist canbe represented by Structural Formula I wherein n is three, M is C(OH)R²,R² is a phenyl group or a halophenyl group (e.g., 4-chlorophenyl) and Zis represented by Structural Formula (VI) wherein X₁ is —CH₂—O—. In oneexample of this embodiment, R⁴⁰ can be —O-(substituted aliphatic group),such as

[0074] In another example, R⁴⁰ can be —COOH.

[0075] In another embodiment, the antagonist of chemokine activity canbe represented by Structural Formula (VII):

[0076] and physiologically acceptable salts thereof.

[0077] n is as described in Structural Formula (I). Z is as describedherein, preferably as described in Structural Formula (V) or (VI).

[0078] M is >NR², >CR¹R², —O—CR1R²—O— or —CH₂—CR¹R²—O—.

[0079] R¹ and R² are as described in Structural Formula (I).

[0080] q¹ is an integer, such as an integer from zero to about three,and q² is an integer from zero to about one. The ring containing M canbe substituted or unsubstituted.

[0081] Thus, the antagonist of chemokine function can be represent by,for example, Structural Formulas (VIIa)-(VIIIk):

[0082] and physiologically acceptable salts thereof, wherein Z, n and Mare as described in Structural Formula (VII), and the ring whichcontains M is substituted or unsubstituted. The ring containing M canhave one or more suitable substituents which are the same or different.Suitable substituents for the ring which contains M and othernonaromatic heterocyclic rings are as described herein. For example, thering containing M can be substituted with a methyl, ethyl, propyl, butylor oxo group.

[0083] The nitrogen atom in the ring containing M can be a tertiarynitrogen as depicted in Structural Formula (IV), or the nitrogen atomcan be quaternized with a suitable substituent, such as a C₁ to about C₆or a C₁ to about C₃ substituted or unsubstituted aliphatic group.Compounds which comprise a quaternary nitrogen atom can also contain acounteranion such as chloride, bromide, iodide, acetate, perchlorate andthe like.

[0084] The antagonist of chemokine function can be represented byStructural Formula (VII) wherein the heterocyclic ring containing M issubstituted with a suitable bivalent group which is bonded to two atomsthat are in the ring, thereby forming a bicyclic moiety. Suitablebivalent groups include, for example, substituted or unsubstitutedbivalent aliphatic groups, such as a C₁-C₆ alkylene group.

[0085] The antagonist of chemokine receptor function can comprise avariety of bicyclic moieties. In one embodiment, the antagonist ofchemokine receptor function can be represented by Structural Formula(VII):

[0086] and physiologically acceptable salts thereof.

[0087] M is >NR², >CR¹R², —O—CR¹R²—O— or —CH₂—CR¹R²—O—. Preferably, M is>NR² or >CR¹R². R¹ and R² are as described in Structural Formula (I),and n and Z are as described in structural Formula (VII).

[0088] In another embodiment, the antagonist of chemokine receptorfunction is represented by Structural Formula (IX):

[0089] and physiologically acceptable salts thereof.

[0090] Z is as described herein, preferably as described in StructuralFormula (V) or (VI).

[0091] n is an integer, such as an integer from one to about four.Preferably, n is one, two or three. More preferably n is two. Inalternative embodiments, other aliphatic or aromatic spacer groups (L)can be employed for (CH₂)_(n).

[0092] R⁵⁰ and R⁵¹ are each independently —H, an aliphatic group, asubstituted aliphatic group, an aminoalkyl group, —NR³R⁴, an aromaticgroup, a substituted aromatic group, a benzyl group, a substitutedbenzyl group, a non-aromatic heterocyclic group, a substitutednon-aromatic heterocyclic group or a covalent bond between the nitrogenatom an adjacent carbon atom.

[0093] R³ and R⁴ are independently —H, an acyl group, a substituted acylgroup, an aliphatic group, a substituted aliphatic group, an aromaticgroup, a substituted aromatic group, a benzyl group, a substitutedbenzyl group, a non-aromatic heterocyclic group or a substitutednon-aromatic heterocyclic group.

[0094] R³ and R⁴ taken together with the atom to which they are bonded,can alternatively form a substituted or unsubstituted non-aromaticcarbocyclic or heterocyclic ring.

[0095] In a preferred embodiment R⁵⁰ is a substituted aliphatic group,such as a substituted C₁ to about C₁₂ alkyl group, and R⁵¹ is —H or asubstitited or unsubstituted aliphatic group. More preferably, R⁵⁰ is asubstituted linear or branched C₂ to about C₇ aliphatic group whereinone or more carbon atoms can be replaced by a heteroatom, such asnitrogen, oxygen or sulfur, and R⁵¹ is —H or a linear or branched C₁ toabout C₆ or a C₁ to about C₃ aliphatic group wherein one or more carbonatoms can be replaced by a heteroatom. R⁵⁰ and R⁵¹ can be substitutedwith one or more suitable substituents, as described herein, Preferablyan aromatic group (e.g., phenyl, 4-halophenyl). For example, R⁵⁰ can beselected from the group consisting of:

[0096] The activity of chemokine receptor antagonists represented byStructural Formula IX can be affected by the character of the nitrogenatom to which R⁵⁰ and R⁵¹ are bonded. It is believed that compounds inwhich said nitrogen atom is basic can have potent chemokine receptorantagonist activity. It is known that the basicity of a nitrogen atomcan be decreased when the nitrogen atom is bonded to a carbonyl group,sulfonyl group or a sulfinyl group. Therefore, it is preferred thatneither R⁵⁰ nor R⁵¹ comprise a carbonyl group, sulfonyl group orsulfinyl group that is directly bonded to the nitrogen atom.

[0097] In another aspect, the antagonist of chemokine receptor functionis represented by Structural Formula (X):

[0098] and physiologically acceptable salts thereof.

[0099] Z is a cycloalkyl or non-aromatic heterocyclic ring group fusedto one, two or more aromatic rings, wherein each ring in Z isindependently substituted or unsubstituted. Preferably, Z is asdescribed in Structural Formula (VI).

[0100] n is an integer, such as an integer from one to about four.Preferably, n is one, two or three. More preferably n is two. Inalternative embodiments, other aliphatic or aromatic spacer groups (L)can be employed for (CH₂)_(n).

[0101] M is >NR² or >CR².

[0102] R² is —H, —OH, an acyl group, a substituted acyl group, —NR⁵R⁶,an aliphatic group, a substituted aliphatic group, an aromatic group, asubstituted aromatic group, a benzyl group, a substituted benzyl group,a non-aromatic heterocyclic group, a substituted non-aromaticheterocyclic group, —O-(substituted or unsubstituted aromatic group) or—O-(substituted or unsubstituted aliphatic group). R² is preferably anaromatic group or a substituted aromatic group.

[0103] R⁵ and R⁶ are independently —H, an acyl group, a substituted acylgroup, an aliphatie group, a substituted aliphatic group, an aromaticgroup, a substituted aromatic group, a benzyl group, a substitutedbenzyl group, a non-aromatic heterocyclic group or a substitutednon-aromatic heterocyclic group.

[0104] R⁵ and R⁶ taken together with the atom to which they are bonded,can alternatively form a substituted or unsubstituted non-aromaticcarbocyclic or heterocyclic ring.

[0105] X⁻ is a physiologically acceptable anion. Preferably, X⁻ is Cl⁻or Br⁻.

[0106] The chemokine receptor antagonist described herein can beprepared and administered as active compounds or as prodrugs. Generally,prodrugs are analogues of pharmaceutical agents which can undergochemical conversion by metabolic processes to become fully active. Forexample, A prodrug of the invention can be prepared by selectingappropriate groups for R⁴⁰. In one embodiment, a prodrug can berepresented by Structural Formula (XI):

[0107] wherein, R⁴⁰ is Q-substituted aliphatic group, and the aliphaticgroup is substituted with —(O)_(u)—(CH₂)_(t)—C(O)OR²⁰, wherein Q is—C(O)O—, u is one, t is zero and R²⁰ is a cyclic aliphatic group. Forexample, when the substituted aliphatic group is a substituted ethylgroup, R⁴⁰ can be represented by:

[0108] Such a prodrug can be converted to an active chemokine receptorantagonist represented by Structural Formula (XI, wherein R⁴⁰ is —COOH.

[0109] Another embodiment of the present invention includes novelcompounds employed in these methods.

[0110] The compounds disclosed herein can be obtained as E- andZ-configurational isomers. It is expressly pointed out that theinvention includes compounds of the E-configuration and theZ-configuration around the double bond connecting Ring C of Z to theremainder of the molecule, and a method of treating a subject withcompounds of the E-configuration, the Z-configuration, and mixturesthereof. Accordingly, in the structural formulas presented herein, thesymbol:

[0111] is used to represent both the E-configuration and theZ-configuration. Preferably Ring A and the alkylene chain bonded to RingC are in the cis configuration. For example, the compounds can have theconfiguration of:

[0112] It is understood that one configuration can have greater activitythan another. The desired configuration can be determined by screeningfor activity, employing the methods described herein.

[0113] Additionally, certain compounds of the invention may be obtainedas different sterioisomers (e.g., diastereomers and enantiomers). It ispointed out that the invention includes all isomeric forms and racemicmixtures of the disclosed compounds and a method of treating a subjectwith both pure isomers and mixtures thereof, including racemic mixtures.Again, it is understood that one sterioisomer may be more active thananother. The desired isomer can be determined by screening.

[0114] Also included in the present invention are physiologicallyacceptable salts of the compounds represented by Structural Formulas (I)through (XI). Salts of compounds containing an amine or other basicgroup can be obtained, for example, by reacting with a suitable organicor inorganic acid, such as hydrogen chloride, hydrogen bromide, aceticacid, citric acid, perchloric acid and the like. Compounds with aquaternary ammonium group also contain a counteranion such as chloride,bromide, iodide, acetate, perchlorate and the like. Salts of compoundscontaining a carboxylic acid or other acidic functional group can beprepared by reacting with a suitable base, for example, a hydroxidebase. Salts of acidic functional groups contain a countercation such assodium, potassium, ammonium, calcium and the like.

[0115] As used herein, aliphatic groups include straight chained,branched or cyclic C₁-C₂₀ hydrocarbons which are completely saturated orwhich contain one or more units of unsaturation. Preferred aliphaticgroups are C₁ to about C₁₀ hydrocarbons. More preferred are C₁ to aboutC₆ or C₁ to about C₃ hydrocarbons. One or more carbon atoms in analiphatic group can be replaced with a heteroatom, such as nitrogen,oxygen or sulfur. For example, suitable aliphatic groups includesubstituted or unsubstituted linear, branched or cyclic C₁-C₂₀ alkyl,alkenyl or alkynyl groups.

[0116] An aminoalkyl group is an alkyl group substituted with —NR²⁴R²⁵,R²⁴ and R²⁵ are as described herein. Preferably the alkyl moietycomprises one to about twelve, more preferably one to about six carbonatoms. The alkyl moiety of an aminoalkyl group can be unsubstituted orsubstituted as described herein for aliphatic groups. Examples ofsuitable aminoalkyl groups include aminomethyl, 2-aminoethyl,3-aminopropyl, 4-aminobutyl, dimethylaminoethyl, diethylaminomethyl,methylaminohexyl, aminoethylenyl and the like.

[0117] Aromatic groups include carbocyclic aromatic groups such asphenyl, 1-naphthyl, 2-naphthyl, 1-anthracyl and 2-anthracyl, andheterocyclic aromatic or heteroaryl groups such as N-imidazolyl,2-imidazolyl, 4-imidazolyl, 5-imidazolyl, 2-thienyl, 3-thienyl,2-furanyl, 3-furanyl, 2-pyrrolyl, 3-pyrrolyl, 2-pyridyl, 3-pyridyl,4-pyridyl, 2-pyrimidyl, 4-pyrimidyl, 5-pyrimidyl, 3-pyridazinyl,4-pyridazinyl, 3-pyrazolyl, 4-pyrazolyl, 5-pyrazolyl, 2-pyrazinyl,2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 5-tetrazolyl, 2-oxazolyl,4-oxazolyl and 5-oxazolyl. Where these rings are fused, for example, toRing C, the stated point of attachment can be either of the two fusedbonds.

[0118] Aromatic groups also include fused polycyclic aromatic ringsystems in which a carbocyclic aromatic ring or heteroaryl ring is fusedto one or more other rings. Examples include tetrahydronaphthyl,2-benzothienyl, 3-benzothienyl, 2-benzofuranyl, 3-benzofuranyl,2-indolyl, 3-indolyl, 2-quinolinyl, 3-quinolinyl, 2-benzothiazolyl,2-benzooxazolyl, 2-benzimidazolyl, 1-isoquinolinyl, 1-isoindolyl,3-isoindolyl, acridinyl, 3-benzisoxazolyl, and the like. Also includedwithin the scope of the tenn “aromatic group”, as it is used herein, isa group in which one or more carbocyclic aromatic rings and/orheteroaryl rings are fused to a cycloalkyl or non-aromatic heterocyclicring, for example, benzocyclopentane, benzocyclohexane.

[0119] Non-aromatic heterocyclic rings are non-aromatic carbocyclicrings which include one or more heteroatoms such as nitrogen, oxygen orsulfur in the ring. The ring can be five, six, seven or eight-memberedand/or fused to another ring, such as a cycloalkyl on aromatic ring.Examples include 1,3-dioxolan-2-yl, 3-1H-benzimidazol-2-one,3-1-alkyl-benzimidazol-2-one, 3-1-methyl-benzimidazol-2-one,2-tetrahydrofuranyl, 3-tetrahydrofuranyl, 2-tetrahyrothiophenyl,3-tetrahyrothiophenyl, 2-morpholino, 3-morpholino, 4-morpholino,2-thiomorpholino, 3-thiomorpholino, 4-thiomorpholino, 1-pyrrolidinyl,2-pyrrolidinyl, 3-pyrrolidinyl, 1-piperazinyl, 2-piperazinyl,1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl,4-thiazolidinyl, diazolonyl, N-substituted diazolonyl, 1-phthalimidyl,1-3-alkyl-phthalimidyl, benzoxane, benzopyrolidine, benzopiperidine,benzoxolane, benzothiolane, benzothiane,

[0120] Suitable substituents on an aliphatic group, aromatic group(carbocyclic and heteroaryl), non-aromatic heterocyclic ring or benzylgroup include, for example, an electron withdrawing group, a halogen,azido, —CN, —COOH, —OH, —CONR²⁴R²⁵, NR²⁴R²⁵, —OS(O)₂ NR²⁴R²⁵,—S(O)₂NR²⁴R²⁵, —SO₃H, —S(O)₂NH₂, guanidino, —(O)_(u)—(CH₂)_(t)—C(O)OR²⁰,—(O)_(u)—(CH₂)_(t)—OC(O)R², —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²²,—(O)_(u)—(CH₂)_(t)—NHC(O)O—R²⁰, —Q—H, —Q-(aliphatic group),—Q-(substituted aliphatic group), —Q-(aryl), —Q-(aromatic group),—Q-(substituted aromatic group), —Q—(CH₂)_(p)-(substituted orunsubstituted aromatic group) p is an integer from 1-5),—Q-(non-aromatic heterocyclic group) or —Q—(CH₂)_(p)-(non-aromaticheterocyclic group).

[0121] R²⁰, R²¹ and R²² are independently —H, an aliphatic group, asubstituted aliphatic group, an aromatic group, a substituted aromaticgroup, a non-aromatic heterocyclic group, —NHC(O)—O-(aliphatic group),—NHC(O)—O-(aromatic group) or —NHC(O)—O-(non-aromatic heterocyclicgroup) and wherein R²¹ and R²², taken together with the nitrogen atom towhich they are bonded, can form a non-aromatic heterocyclic ring. t isan integer from zero to about three, and the methylene group,—(CH₂)_(t)—, can be substituted, as described herein for aliphaticgroups, or unsubstituted.

[0122] u is zero or one.

[0123] Q is —O—, —S—, —S(O)—, —S(O)₂—, —OS(O)₂—, —C(O)—, —OC(O)—,—C(O)O—, —C(O)C(O)—O—, —O—C(O)C(O)—, —C(O)NH—, —NHC(O)—, —OC(O)NH—,—NHC(O)O—, —NH—C(O)—NH—, —S(O)₂NH—, —NHS(O)₂—, —N(R²³)—, —C(NR²³)NHNH—,—NHNHC(NR²³)—, —NR²⁴C(O)— or —NR²⁴S(O)₂—.

[0124] R²³ is —H, an aliphatic group, a benzyl group, an aryl group ornon-aromatic heterocyclic group.

[0125] R²⁴ and R²⁵ are independently —H, —OH, an aliphatic group, asubstituted aliphatic group, a benzyl group, an aryl group, non-aromaticheterocyclic group or R²⁴ and R²⁵ taken together with the nitrogen atomto which they are bonded can form a substituted or unsubstitutednon-aromatic heterocyclic ring.

[0126] A substituted non-aromatic heterocyclic ring, benzyl group oraromatic group can also have an aromatic group, an aliphatic orsubstituted aliphatic group, as a substituent. When a non-aromatic ring(carbocyclic or heterocyclic) or an aromatic ring (carbocyclic aromaticor heteroaryl) is substituted with another ring, the two rings can befused. A substituted aliphatic group can also have an oxo group, epoxygroup, non-aromatic heterocyclic ring, benzyl group, substituted benzylgroup, aromatic group or substituted aromatic group as a substituent. Asubstituted non-aromatic heterocyclic ring can also have ═O, ═S, ═NH or═N(aliphatic, aromatic or substituted aromatic group) as a substituent.A substituted aliphatic, substituted aromatic, substituted non-aromaticheterocyclic ring or substituted benzyl group can have more than onesubstituent, which can be the same or different.

[0127] Acyl groups include substituted and unsubstituted aliphaticcarbonyl, aromatic carbonyl, aliphatic sulfonyl and aromatic sulfonyl.

[0128] Suitable electron withdrawing groups include, for example,alkylimines, alkylsulfonyl, carboxamido, carboxylic alkyl esters,—CH═NH, —CN, —NO₂ and halogens.

[0129] In the structural formulas depicted herein, the single or doublebond by which a chemical group or moiety is connected to the remainderof the molecule or compound is indicated by the following symbol:

[0130] For example, the corresponding symbol in Structural Formulas(II), (III) and (IV) indicates the double bond by which the central ringof the tricyclic ring system is connected to the remainder of themolecule represented by Structural Formula (I).

[0131] A “subject” is preferably a bird or mammal, such as a human, butcan also be an animal in need of veterinary treatment, e.g., domesticanimals (e.g., dogs, cats, and the like), farm animals (e.g., cows,sheep, fowl, pigs, horses, and the like) and laboratory animals (e.g.,rats, mice, guinea pigs, and the like).

[0132] An “effective amount” of a compound is an amount which results inthe inhibition of one or more processes mediated by the binding of achemokine to a receptor in a subject with a disease associated withaberrant leukocyte recruitment and/or activation. Examples of suchprocesses include leukocyte migration, integrin activation, transientincreases in the concentration of intracellular free calcium [Ca²⁺], andgranule release of proinflammatory mediators. Alternatively, an“effective amount” of a compound is a quantity sufficient to achieve adesired therapeutic and/or prophylactic effect, such as an amount whichresults in the prevention of or a decrease in the symptoms associatedwith a disease associated with aberrant leukocyte recruitment and/oractivation.

[0133] The amount of compound administered to the individual will dependon the type and severity of the disease and on the characteristics ofthe individual, such as general health, age, sex, body weight andtolerance to drugs. It will also depend on the degree, severity and typeof disease. The skilled artisan will be able to determine appropriatedosages depending on these and other factors. Typically, an effectiveamount of the compound can range from about 0.1 mg per day to about 100mg per day for an adult. Preferably, the dosage ranges from about 1 mgper day to about 100 mg per day. An antagonist of chemokine receptorfunction can also be administered in combination with one or moreadditional therapeutic agents, e.g. theophylline, β-adrenergicbronchodilators, corticosteroids, antihistamines, antiallergic agents,immunosuppressive agents (e.g., cyclosporin A, FK-506, prednisone,methylprednisolone) and the like.

[0134] The compound can be administered by any suitable route,including, for example, orally in capsules, suspensions or tablets or byparenteral administration. Parenteral administration can include, forexample, systemic administration, such as by intramuscular, intravenous,subcutaneous, or intraperitoneal injection. The compound can also beadministered orally (e.g., dietary), transdermally, topically, byinhalation (e.g., intrabronchial, intranasal, oral inhalation orintranasal drops), or rectally, depending on the disease or condition tobe treated. Oral or parenteral administration are preferred modes ofadministration.

[0135] The compound can be administered to the individual in conjunctionwith an acceptable pharmaceutical or physiological carrier as part of apharmaceutical composition for treatment of HIV infection, inflammatorydisease, or the other diseases discussed above. Formulation of acompound to be administered will vary according to the route ofadministration selected (e.g., solution, emulsion, capsule). Suitablecarriers may contain inert ingredients which do not interact with thecompound. Standard pharmaceutical formulation techniques can beemployed, such as those described in Remington's PharmaceuticalSciences, Mack Publishing Company, Easton, Pa. Suitable carriers forparenteral administration include, for example, sterile water,physiological saline, bacteriostatic saline (saline containing about0.9% benzyl alcohol), phosphate-buffered saline, Hank's solution,Ringer's-lactate and the like. Methods for encapsulating compositions(such as in a coating of hard gelatin or cyclodextran) are known in theart (Baker, et al., “Controlled Release of Biological Active Agents”,John Wiley and Sons, 1986).

[0136] The activity of compounds of the present invention can beassessed using suitable assays, such as receptor binding assays andchemotaxis assays. For example, as described in the ExemplificationSection, small molecule antagonists of RANTES and MIP-1 a binding havebeen identified utilizing THP-1 cells which bind RANTES and chemotax inresponse to RANTES and MIP-1α as a model for leukocyte chemotaxis.Specifically, a high through-put receptor binding assay, which monitors¹²⁵I-RANTES and ¹²⁵I-MIP-1α binding to THP-1 cell membranes, was used toidentify small molecule antagonists which block binding of RANTES andMIP-1α. Compounds of the present invention can also be identified byvirtue of their ability to inhibit the activation steps triggered bybinding of a chemokine to its receptor, such as chemotaxis, integrinactivation and granule mediator release. They can also be identified byvirtue of their ability to block RANTES and MIP-1α mediated HL-60,T-cell, peripheral blood mononuclear cell, and eosinophil chemotacticresponse.

[0137] The compounds disclosed herein can be prepared accordingly to theschemes shown in FIGS. 1-5 and 7. The schemes are described in greaterdetail below.

[0138]FIG. 1 shows the preparation of compounds represented byStructural Formula (1). L¹ is PPh₃Cl, PPh₃Br, PPh₃I or (EtO)₂P(O), L² isa suitable leaving group such as halogen, p-toluene sulfonate, mesylate,alkoxy, and phenoxy; Pg is a suitable protecting group such astetrahydropyranyl; and the other symbols are as defined above.

[0139] In Step 1 of FIG. 1, a Wittig reaction is carried out in asolvent such as ether, or tetrahydrofuran (THF) in the presence of abase such as sodium hydride, n-butyl lithium or lithium diisopropylamide(LDA) at 0° C. up to the reflux temperature for the solvent used for 5minutes to 72 h. Compounds represented by Formula II in FIG. 1 can beprepared by methods disclosed in JP 61/152673, U.S. Pat. No. 5,089,496,WO 89/10369, WO 92/20681 and WO 93/02081, the entire teachings of whichare incorporated herein by reference.

[0140] In Step 2 of FIG. 1, deprotection is carried out with an acid ina solvent such as methanol at room temperature up to the refluxtemperature for the solvent used for 5 minutes to 72 h. Alternatively, acompound of represented by Formula V in FIG. 1 can be prepared directlyfrom step 1 without isolating an intermediate. The reaction mixtureobtained after the work up of the reaction described in step 1 can bedissolved in the solvent and reacted with the acid.

[0141] In Step 3 of FIG. 1, the hydroxy group can be converted to aleaving group by known methods. Compounds represented by Formula VI inFIG. 1 can be prepared by methods disclosed in J. Med. Chem., 1992 (35)2074-2084 and JP 61/152673.

[0142] In Step 4 of FIG. 1, an alkylation reaction is carried out in asolvent such as acetone, methyl ethyl ketone, ethyl acetate, toluene,tetrahydrofuran (THF) or dimethylformamide (DMF) in the presence of abase such as potassium carbonate or sodium hydride and a catalyst suchas an alkali metal iodide at room temperature up to the refluxtemperature for the solvent used for 5 minutes to 72 h.

[0143]FIG. 2 shows the preparation of compounds represented by Compound(VI-b). In Step 1 of FIG. 2, a Grignard reaction may be carried out in asolvent such as ether, or tetrahydrofuran (THF) at 0° C. up to thereflux temperature for the solvent used for 5 minuets to 72 h. CompoundVII is available commercially.

[0144] In Step 2 of FIG. 2, bromination may be carried out withbrominate agents such as hydrobromic acid, bromotrimethylsilane or borontribromide-methyl sulfide complex in a solvent such as acetic acid,dichloromethane or dichloroethane at room temperature up to the refluxtemperature for the solvent used for 5 minutes to 72 h.

[0145]FIG. 3 shows the preparation of compounds represented byStructural Formula (I). In FIG. 3, a reductive amination may be carriedout with reducing regents such as sodium cyanoborohydride, sodiumacetoxyborohydride or sodium borohydride in a solvent such as methanol,ethanol, tetrahydrofuran (THF), dichloromethane or dichloroethane atroom temperature up to the reflux temperature for the solvent used for 5minutes to 72 h.

[0146]FIG. 4 shows the preparation of compounds represented byStructural Formula (I), where in Z is represented by Structural Formulas(III) and wherein Ring A and/or Ring B in Z is substituted with R⁴⁰. InFIG. 4, the alkylation reaction can be carried out in a solvent such asacetone, methyl ethyl ketone, ethyl acetate, toluene, tetrahydrofuran(THF) or dimethylformamide (DMF) in the presence of a base such aspotassium carbonate or sodium hydride and a catalyst such as an alkalimetal iodide at room temperature up to the reflux temperature for thesolvent used for 5 minutes to 72 h.

[0147]FIG. 5 is a schematic showing the preparation of the compoundsrepresented by Structural Formula (I), wherein Z is represented byStructural Formulas (III) and wherein Ring A and/or Ring B in Z issubstituted with —(O)_(u)—(CH₂)_(t)—COOR²⁰, —(O)_(u)—(CH₂), —OC(O)R²,—(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)O—R²⁰. InFIG. 5, the hydrolysis reaction may be carried out in a mixture ofaqueous alkali metal hydroxide solution and a solvent such as methanol,ethanol, tetrahydrofuran (THF) or dioxane at room temperature up to thereflux temperature for the solvent used for 5 minutes to 72 h. Theacylation reaction can be carried out using dicyclohexylcarbodiimide(DCC) or (1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (DEC) in asolvent such as tetrahydrofuran (THF), dimethylformamide (DMF) ormethylene chloride in the presence of a base such as pyridine ortriethylamine (when necessary) at temperatures of 0 to 1 00° C. for 5minutes to 72 h.

[0148]FIG. 7 shows the preparation of compounds represented byStructural Formula (I), wherein Z is represented by Structural Formulas(III) and wherein Ring A or Ring B in Z is substituted with R⁴⁰. L4 is asuitable leaving group such as halogen or trifluoromethylsulfonate. InFIG. 7, a palladium coupling reaction such as Stille coupling, Suzukicoupling, Heck reaction, or carboxylation using carbon monoxide may becarried out using a palladium catalyst such astetrakis(triphenylphosphine)palladium, bis(triphenylphosphine)palladiumchloride, and palladium acetate in a solvent such as tetrahydrofuran(THF), 1,4-dioxane, toluene, dimethylformamide (DMF), ordimethylsufoxide (DMSO) in the presence of additive (when necessary)such as triphenylphosphine, 1,1′-bis(diphenylphosphino)ferrocene,triethylamine, sodium bicarbonate, tetraethylammonium chloride, orlithium chloride at room temperature up to the reflux temperature forthe solvent used for 5 minutes to 72 h. FIG. 10C shows three proceduresfor the preparation of compounds represented by Structural Formulas (I),(VII), (VIII) and (IX), wherein Z is represented by Structural Formula(III) and wherein Ring A or Ring B in Z is substituted with R⁴⁰. In FIG.10C, R⁴⁰ is represented by —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²², u is one, tis zero.

[0149] In FIG. 10C a compound containing a phenol can be reacted with acarbonate equivalent, such as a carbamoyl chloride (method A), anisocyanate (method B) or an acylimidazole (method C), in the presence ofa base such as sodium hydroxide, potassium carbonate or sodium carbonatein a solvent such as dimethylformamide or tetrahydrofuran, at atemperature from 0° C. to reflux temperature for a period of about 5minutes to about 72 hours.

[0150] Compounds represented by Structural Formula (I), wherein Z isrepresented by Structural Formulas (III) or (IV), X is —CO—NR_(c)— andR_(c) is —(CH₂)_(s)—COOR³⁰, —(CH₂)_(s)—C(O)—NR³¹R³² or—(CH₂)_(s)—NHC(O)—O—R³, can be prepared by suitable modification of thescheme shown in FIGS. 1-5 and 7. One modification utilizes the startingmaterial shown in FIG. 1, wherein X is —CO—NH—. The amide is thenalkylated with L³—(CH₂)_(s)—COOR³⁰, wherein L³ is a suitable leavinggroup, using the alkylation procedures described above. The remainder ofthe synthesis is as described in FIGS. 1-5 and 7.

[0151] Although FIGS. 1-5 and 7 show the preparation of compounds inwhich Rings A and B are phenyl rings, analogous compounds withheteroaryl groups for Rings A and B can be prepared by using startingmaterials with heteroaryl groups in the corresponding positions. Thesestarting materials can be prepared according to methods disclosed in JP61/152673, U.S. Pat. No. 5,089,496, WO 89/10369, WO 92/20681 and WO93/02081.

[0152] The invention is illustrated by the following examples which arenot intended to be limiting in any way.

EXEMPLIFICATION EXAMPLE 1

[0153]4-(4-Chlorophenyl)-1-[3-(10,11-dihydro-5H-dibenzo[a,d]cycloheptene-5-ylidene)propyl]piperidin-4-ol

[0154] To a solution of5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene(described in JP 48-030064)(200 mg) in DMF (10 ml) were added 4-(4-chlorophenyl)-4-hydroxypiperidine (230 mg), potassium carbonate (360mg), and potassium iodide (50 mg). The mixture was stirred at 70° C. for24 hours. Water and ethyl acetate were added to the reaction mixture,the organic layer was separated and washed with saturated aqueous sodiumchloride, and dried with magnesium sulfate. The solvent was distilledoff under reduced pressure. The residue was purified by silica gelchromatography eluting with ethyl acetate-hexane (1:1) to give thetitled compound (250 mg). ¹H-NMR (CDCl₃) δ: 1.65-2.11 (5H, m), 2.32-3.10(8H, m), 3.22-3.67 (4H, m), 5.87 (1H, t), 7.03-7.44 (12H, m). MS m/z:444 (M+1).

EXAMPLE 2

[0155]4-(4-Chlorophenyl)-1-[3-(6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol

[0156] The titled compound was prepared by following the procedure ofExample 1, but replacing 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene with11-(3-bromopropylidene)-6,1 1-dihydrodibenz[b,e] oxepine. ¹H-NMR (CDCl₃)δ: 1.61-2.16 (5H, m), 2.37-2.80 (8H, m), 5.22 (2H, brs), 5.70 (0.6×1H,t), 6.03 (0.4×1H, t), 6.73-6.90 (2H, m), 7.09-7.45 (10H, m). MS m/z: 446(M+1)

EXAMPLE 3 Membrane Preparations for Chemokine Binding and Binding Assays

[0157] Membranes were prepared from THP-1 cells (ATCC #TIB202). Cellswere harvested by centrifugation, washed twice with PBS(phosphate-buffered saline), and the cell pellets were frozen at −70 to−85° C. The frozen pellet was thawed in ice-cold lysis buffer consistingof 5 mM HEPES (N-2-hydroxyethylpiperazine-N′-2-ethane-sulfonic acid) pH7.5, 2 mM EDTA (ethylenediaminetetraacetic acid), 5 μg/ml eachaprotinin, leupeptin, and chymostatin (protease inhibitors), and 100μg/ml PMSF (phenyl methane sulfonyl fluoride—also a protease inhibitor),at a concentration of 1 to 5×10⁷ cells/ml. This procedure results incell lysis. The suspension was mixed well to resuspend all of the frozencell pellet. Nuclei and cell debris were removed by centrifugation of400× g for 10 minutes at 4° C. The supernatant was transferred to afresh tube and the membrane fragments were collected by centrifugationat 25,000× g for 30 minutes at 4° C. The supernatant was aspirated andthe pellet was resuspended in freezing buffer consisting of 10 mM HEPESpH 7.5, 300 mM sucrose, 1 g/ml each aprotinin, leupeptin, andchymostatin, and 10 μg/ml PMSF (approximately 0.1 ml per each 10⁸cells). All clumps were resolved using a minihomogenizer, and the totalprotein concentration was determined using a protein assay kit (Bio-Rad,Hercules, Calif., cat #500-0002). The membrane solution was thenaliquoted and frozen at −70 to −85° C. until needed.

[0158] Binding Assays utilized the membranes described above. Membraneprotein (2 to 20 μg total membrane protein) was incubated with 0.1 to0.2 nM ¹²⁵I-labeled RANTES or MIP-1α with or without unlabeledcompetitor (RANTES or MIP-1α) or various concentrations of compounds.The binding reactions were performed in 60 to 100 μl of a binding bufferconsisting of 10 mM HEPES pH 7.2, 1 mM CaCl₂, 5 mM MgCl₂, and 0.5% BSA(bovine serum albumin), for 60 min at room temperature. The bindingreactions were terminated by harvesting the membranes by rapidfiltration through glass fiber filters (GF/B or GF/C, Packard) whichwere presoaked in 0.3% polyethyleneimine. The filters were rinsed withapproximately 600 μl of binding buffer containing 0.5 M NaCl, dried, andthe amount of bound radioactivity was determined by scintillationcounting in a Topcount beta-plate counter.

[0159] The activities of test compounds are reported in the Table belowas IC₅₀ values or the inhibitor concentration required for 50%inhibition of specific binding in receptor binding assays using¹²⁵I-RANTES or ¹²⁵I-MIP— a as ligand and THP-1 cell membranes. Specificbinding is defined as the total binding minus the non-specific binding;non-specific binding is the amount of cpm still detected in the presenceof excess unlabeled Rantes or MIP-1α. TABLE BIOLOGICAL DATA Example IC₅₀(μM)  1   <1  2   <1  8   <1  12   <1  17  <10  18   <1  19   <1  21  <1  22   <1  23   <1  24  <10  25   <1  26   <1  27   <1  28   <1  29  <1  30   <1  31   <1  32   <1  33   <1  34   <1  35   <1  36   <1  38  <1  39  <10  40   <1  41   <1  42   <1  43  <10  44   <1  45   <1  46  <1  47   <1  48   <1  49   <1  51   <1  52   <1  53   <1  54   <1  55  <1  56   <1  57  <10  59   <1  60   <1  61  <10  62  <10  63  <10  64  <1  65   <1  66 <1000  67   <1  68  <10  69   <1  71   <1  72  <10  73 <10  74 <1000  75  <10  76  <10  77   <1  78   <1  79   <1  83 <1000 85   <1  86  >10  89  >10  90   <1  91   <1 111   <1 114   <1 117   <1118   <1 120   <1 122   <1 123   <1 128   <1 130   <1 131   <1 132   <1133   <1 134   <1 135   <1 138   <1 139   <1 140  >10 141   <1 142  <10143   <1 144   <1 145  <10 146  >10 147  <10 148  <10 149 <1000 150  <10151   <1 152   <1 153   <1 154   <1 155   <1 158   <1 159   <1 160   <1161  <10 162   <1 163   <1 166  <10 167   >1 168     1 172   <1 173   <1174   <1 175   <1 176   <1 178   <1 180   <1 181   <1 182   <1 183   <1184  <10 185 <1000 186   <1 187   <1 188  >10 190  >10 191  >10 192  >10193   <1 194   <1 195  <10 197   <1 198   <1 199   <1 200   <1 201   <1203   <1 204   <1 205   <1 211   <1 212   <1 215   <1 216   <1 218   <1242   <1 248  <10 249   <1 262   <1 263   <1 264   <1 265   <1 266   <1267   <1 268   <1 269   <1 270   <1 271   <1 272   <1 273   <1 277   <1278   <1 279   <1 280   <1 281   <1 282   <1 283   <1 284   <1 285   <1286   <1 287   <1 288   <1 289   <1 290   <1 291   <1 292   <1

EXAMPLE 84-(4-Chlorophenyl)-1-[3-(6,11-dihydro-dibenz[b,e]thiepin-11-ylidene)propyl]piperidin-4-ol

[0160] Step 1

[0161] 11-(3-Bromopropylidene)-6,11-dihydrodibenz[b,e]thiepine wasprepared by following the procedure of example 45, step 1 and 2, butreplacing 5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepin-5-one with6,11-dihydrodibenz[b,e]thiepin-11-one.

[0162]¹H-NMR (CDCl₃) δ: 2.50-2.64 (2H, m), 3.36-3.47 (3H, m), 4.99 (1H,d), 5.94 (1H, t), 6.98-7.31 (8H, m).

[0163] Step 2

[0164] The titled compound was prepared by following the procedure ofexample 45, step 3 but replacing5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene withthe product of step 1.

[0165]¹H-NMR (CDCl₃) δ: 1.65-1.80 (3H, m), 1.95-2.70 (10H, m), 3.35 (1H,d), 4.98 (1H, d), 5.96 (1H, t), 7.09-7.43 (12H, m).

[0166] MS m/z: 462 (M+1)

EXAMPLE 121-[3-(5-Benzyl-6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol

[0167] To a solution4-(4-chlorophenyl)-1-[3-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]piperidin-4-ol hydrochloride (Example 39)(300 mg) inDMF (5 ml) were added sodium hydride (60% in oil, 200 mg), benzylbromide (0.1 5 ml) and the mixture was stirred at room temperature for 1hour. Water and ethyl acetate were added to the reaction mixture, theorganic layer was separated and washed with saturated aqueous sodiumchloride, and dried with magnesium sulfate. The solvent was distilledoff under reduced pressure. The residue was purified by silica gelchromatography eluting with ethyl acetate to give the titled compound(180 mg).

[0168]¹H-NMR (CDCl₃) δ: 1.62-1.67 (2H, m), 1.99-2.20 (3H, m), 2.33-2.65(8H, m), 5.10 (1H, d), 5.75 (1H, d), 5.94 (1H, t), 7.11-7.42 (16H, m),7.91 (1H, dd). MS m/z: 549 (M+1)

EXAMPLE 171-[3-(5-Carboxymethyl-6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol

[0169]4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-5-ethoxycarbonylmethyl-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]piperidin-4-ol(Example 18)(1.0 g) was solved in 1M hydrogen chloride in diethyl etherand stirred at room temperature for 24 hours.

[0170] Aqueous sodium hydroxide and ethyl acetate were added to thereaction mixture, the aqueous layer was separated and neutralized withdilute hydrochloric acid. The precipitation was filtered to give thetitled compound (250 mg).

[0171]¹H-NMR (DMSO-d₆) δ: 1.44-1.61 (2H, m), 2.07-2.17 (1H, m),2.35-3.01 (9H, m), 4.28 (1H, d), 4.59 (1H, d), 5.83 (1H, t), 7.18-7.71(12H, m). MS m/z: 517 (M+1)

EXAMPLE 184-(4-Chlorophenyl)-1-[3-(6,11-dihydro-5-ethoxycarbonymetyl-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]piperidin-4-ol

[0172] The titled compound was prepared by following the procedure ofexample 1, but replacing5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene with11-(3-bromopropylidene)-5-ethoxycarbonymetyl-6-oxo-5H-dibenz[b,e]azepine.

[0173]¹H-NMR (CDCl₃) δ: 1.30 (3H, t), 1.64-1.69 (2H, m), 1.97-2.10 (3H,m), 2.38-2.71 (8H, m), 4.27 (2H, q), 4.32 (1H, d), 4.84 (1H, d), 5.88(1H, t), 7.16-7.45 (1H, m), 7.88 (1H, dd).

[0174] MS m/z: 545 (M+1)

EXAMPLE 19

[0175]4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-5-methyl-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]piperidin-4-ol

[0176] The titled compound was prepared by following the procedure ofExample 1, but replacing5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene with11-(3-bromopropylidene)-5-methyl-6-oxo-5H-dibenz[b,e]azepin.

[0177]¹H-NMR (CDCl₃) δ: 1.58-2.06 (5H, m), 2.39-2.75 (8H, m), 3.53 (3H,s), 5.84 (1H, t), 7.10-7.44 (11H, m), 7.85-7.89 (1H, m). MS m/z: 473(M+1).

EXAMPLE 214-(4-Chlorophenyl)-1-[3-(5H-dibenzo[a,d]cycloheptene-5-ylidene)propyl]piperidin-4-ol

[0178] The titled compound was prepared by following the procedure ofexample 1, but replacing 5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene with5-(3-bromopropylidene)-5H-dibenzo[a,d]cycloheptene.

[0179]¹H-NMR (CDCl₃) δ: 1.58-1.63 (2H, m), 2.00-2.05 (2H, m), 2.26-2.46(6H, m), 2.62-2.66 (2H, m), 5.55 (1H, t), 6.85 (2H, s), 7.24-7.40 (12H,m).

[0180] MS m/z: 442 (M+1).

EXAMPLE 224-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-methoxycarbonyldibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol

[0181] The titled compound was prepared by following the procedure ofexample 1, but replacing5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene with11-(3-bromopropylidene)-6,11-dihydro-2-methoxy-carbonyldibenz[b,e]oxepine.

[0182]¹H-NMR (CDCl₃) δ: 1.65-1.70 (2H, m), 2.01-2.13 (3H, m), 2.41-2.80(7H, m), 3.85 (3H, s), 5.40 (2H, brs), 5.73 (0.6×1H, t), 6.09 (0.4×1H,t), 6.76 (0.6×1H, d), 6.82 (0.4×1H, d), 7.21-7.43 (8H, m), 7.73 (1H,dd), 7.87 (0.6×1H, d), 7.97 (0.4×1H, d).

[0183] MS m/z: 504 (M+1).

EXAMPLE 231-[3-(2-Butoxycarbonyl-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0184] The titled compound was prepared by following the procedure ofexample 1, but replacing5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene with11-(3-bromopropylidene)-2-butoxy-6,11-dihydrodibenz[b,e]oxepine.

[0185]¹H-NMR (CDCl₃) δ: 0.96 (3H, t), 1.53 (2H, q), 1.70-1.77 (3H, m),2.02-2.14 (3H, m), 2.39-2.78 (5H, m), 4.27 (2H, t), 5.27 (2H, brs), 5.75(0.8×1H, t), 6.10 (0.2×1H, t), 6.78 (1H, d), 7.27-7.43 (8H, m), 7.76(1H, dd), 7.89 (0.8×1H, d), 7.98 (0.2×1H, d).

[0186] MS m/z: 546 (M+1).

EXAMPLE 241-[3-(2-Carboxyl-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0187] To a solution of4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-methoxycarbonyldibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol(Example 22)(100 mg) in ethanol (3 ml) were added 15% sodiun hydroxideaqueous solution (0.6 ml) and the mixture was heated to reflux for 12hours. The solvent was distilled off under reduced pressure. Water andethyl acetate were added to the reaction mixture, the aqueous layer wasseparated and neutralized with dilute hydrochloric acid. Theprecipitation was filtered to give the titled compound (80 mg).

[0188]¹H-NMR (CD₃OD) δ: 1.73-1.79 (2H, m), 2.14-2.19 (2H, m), 2.80-2.93(3H, m), 3.02-3.11 (3H, m), 3.24-3.29 (2H, m), 5.25 (2H, brs), 5.61(0.7×1H, t), 6.05 (0.3×1H, t), 6.72 (1H, d), 7.22-7.40 (8H, m),7.52-7.65 (1H, m), 7.75 (0.7×1H, d), 7.80 (0.3×1H, d). MS m/z: 490(M+1).

EXAMPLE 25 4-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-dimethylaminocarbonyldibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol

[0189] The titled compound was prepared by following the procedure ofexample 1, but replacing5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene with11-(3-bromopropylidene)-2-dimethylaminocarbonyl-6,11-dihydrodibenz[b,e]oxepine.

[0190]¹H-NMR (CDCl₃) δ: 1.62-1.67 (2H, m), 2.00-2.12 (2H, m), 2.37-2.47(8H, m), 2.89 (6H, s), 5.25 (2H, brs), 5.68 (0.7×1H, t), 6.03 (0.3×1H,t), 6.71 (0.3×1H, d), 6.78 (0.7×1H, d), 7.13-7.40 (10H, m).

[0191] MS m/z: 517 (M+1).

EXAMPLE 264-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-hydroxymethyldibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol

[0192] To a solution of(4-chlorophenyl)-1-[3-(6,11-dihydromethoxycarbonyldibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol(11 0 mg) in THF (8 ml) were added lithium aluminum hydride (1.0M, 0.42ml) dropwise at 0° C., and the mixture was stirred at room temperaturefor 1 hour. Aqueous sodium hydroxide (IM) was added to the reactionmixture to stir for 30 minutes, then ethyl acetate and brine was addedto the mixture. The organic layer was separated and washed withsaturated aqueous sodium chloride, and dried with magnesium sulfate. Thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel chromatography eluting withdichloromethane-methanol (10:1) to give the titled compound (90 mg).

[0193]¹H-NMR (CDCl₃) δ: 1.61-1.66 (2H, m), 1.98-2.03 (2H, m), 2.39-2.48(3H, m), 2.57-2.79 (6H, m), 4.52 (2H, s), 5.20 (2H, brs), 5.66 (0.8×1H,t), 6.01 (0.2×1H, t), 6.67 (0.2×1H, d), 6.79 (0.8×1H, d), 7.06 (1H, dd),7.15-7.37 (9H, m).

[0194] MS m/z: 476 (M+1).

EXAMPLE 274-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-(1-hydroxy-1-methyl)ethyldibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol

[0195] To a solution of4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-methoxycarbonyldibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol(60 mg) in THF (6 ml) were added methylmagnesium chloride (3.0M, 0.1 6ml) dropwise at 0° C., and the mixture was stirred at room temperaturefor 2 hour, the reaction mixture was quenched by saturated ammoniumaqueous, then ethyl acetate and water was added to the mixture. Theorganic layer was separated and washed with saturated aqueous sodiumchloride, and dried with magnesium sulfate. The solvent was distilledoff under reduced pressure. The residue was purified by silica gelchromatography eluting with ethyl acetate-methanol (95:5) to give thetitled compound (20 mg).

[0196]¹H-NMR (CDCl₃) δ: 1.54 (0.7×6H, s), 1.62 (0.3×6H, s), 1.63-1.70(2H, m), 2.03-2.10 (3H, m), 2.38-2.49 (3H, m), 2.62-2.82 (4H, m), 5.17(2H, brs), 5.68 (0.7×1H, t), 6.05 (0.3×1H, t), 6.75 (0.3×1H, d), 6.83(0.7×1H, d), 7.18-7.43 (10H, m).

[0197] MS m/z: 504 (M+1).

EXAMPLE 284-(4-Chlorophenyl)-1-[3-(2-cyano-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol

[0198] The titled compound was prepared by following the procedure ofexample 1, but replacing5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene with11-(3-bromopropylidene)-2-cyano-6,11-dihydrodibenz[b,e]oxepine.

[0199]¹H-NMR (CDCl₃) δ: 1.67-1.72 (2H, m), 2.02-2.13 (2H, m), 2.37-2.77(8H, m), 5.35 (2H, brs), 5.75 (0.7×1H, t), 6.07 (0.3×1H, t), 6.78(0.3×1H, d), 6.82 (0.7×1H, d), 7.25-7.51 (1 OH, m).

[0200] MS m/z: 471 (M+1).

EXAMPLE 291-[3-(2-Aminomethyl-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0201] To a solution of4-(4-chlorophenyl)-1-[3-(2-cyano-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (380 mg) in EtOH (20 ml) were addedRaney nickel (50% slurry in water, 60 mg), and the mixture washydrogenated at 15 psi for 2 hours. The mixture was filtered through thecelite and distilled off under reduced pressure. The residue waspurified by silica gel chromatography eluting withdichloromethane-methanol-aqueous ammonium (95:5:1) to give the titledcompound (130 mg).

[0202]¹H-NMR (CDCl₃) δ: 1.76-1.94 (3H, m), 2.18-2.34 (2H, m), 2.85-3.10(8H, m), 3.88 (2H, s), 5.30 (2H, brs), 5.59 (1H, t), 6.78 (1H, d),7.13-7.40 (10H, m).

[0203] MS m/z: 475 (M+1).

EXAMPLE 304-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-nitrodibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol

[0204] The titled compound was prepared by following the procedure ofexample 1, but replacing5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene with11-(3-bromopropylidene)-6,11-dihydro-2-nitorodibenz[b,e]oxepine.

[0205]¹H-NMR (CDCl₃) δ: 1.62-1.67 (2H, m), 1.80-2.12 (3H, m), 2.28-2.78(8H, m), 5.05 (0.3×2H, brs), 5.40 (0.7×2H, brs), 5.90 (0.7×1H, t), 6.17(0.3×1H, t), 6.82 (0.3×1H, d), 6.92 (0.7×1H), 7.28-7.41 (8H, m), 7.82(1H, dd), 8.15 (0.7×1H, d), 8.22 (0.3×1H, d).

[0206] MS m/z: 491 (M+1).

EXAMPLE 311-[3-(2-Amino-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0207] To a solution of4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-nitrodibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol(120 mg) in EtOH (15 ml) were added tin (11) chloride (190 mg), and themixture was heated to reflux for 1 hour. The solvent was distilled offunder reduced pressure. To the residue was added ethyl acetate andsodium aqueous to neutralize. The organic layer was separated and washedwith saturated aqueous sodium chloride, and dried with magnesiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was purified by silica gel chromatography eluting withdichloromethane-methanol (95:5) to give the titled compound (70 mg).

[0208]¹H-NMR (DMSO-d₆) δ: 1.54-1.60 (2H, m), 1.85-2.00 (2H, m),2.30-2.80 (8H, m), 3.88 (2H, s).5.07 (2H, brs), 5.66 (1H, t), 6.41-6.46(2H, m), 6.59 (1H, d), 7.24-7.49 (8H, m).

[0209] MS m/z: 461 (M+1).

EXAMPLE 324-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-hydroxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol

[0210] Step 1

[0211] 11-(3-Bromopropylidene)-6,11-dihydro-2-hydroxydibenz[b,e]oxepinewas prepared by following the procedure of example 45, step 1 and 2, butreplacing 5,11-dihydro-7-methoxypyrido [2,3-c][1]benzoxepin-5-one with6,11-dihydro-2-hydroxydibenz[b,e]oxepin-11-one.

[0212]¹H-NMR (CDCl₃) δ: 2.69 (2H, q), 3.39 (2H, t), 5.20 (2H, brs), 5.92(1H, t), 6.50-6.81 (4H, m), 7.17-7.37 (4H, m).

[0213] Step 2

[0214] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene withthe product of step 1.

[0215]¹H-NMR (CDCl₃) δ: 1.60-1.75 (3H, m), 1.95-2.10 (2H, m), 2.35-2.80(8H, m), 5.10 (2H, brs), 5.93 (1H, t), 6.56 (2H, brs), 6.71 (1H, brs),7.11-7.35 (8H, m).

[0216] MS m/z: 462 (M+1)

EXAMPLE 334-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-methoxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol

[0217] Step 1

[0218]11-(3-Bromopropylidene)-6,1 1-dihydro-2-methoxydibenz[b,e]oxepinewas prepared by following the procedure of example 45, step 1 and 2, butreplacing 5,11-dihydro-7-methoxypyrido[2,3-c][1]bcnzoxepin-5-one with6,11-dihydro-2-methoxydibenz[b,e]oxepin-11-one.

[0219]¹H-NMR (CDCl₃) δ: 2.74 (2H, q), 3.43 (2H, t), 3.77 (3H, s), 5.10(2H, brs), 6.02 (1H, t), 6.70-6.83 (3H, m), 7.21-7.38 (4H, m).

[0220] Step 2

[0221] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene withthe product of step 1.

[0222]¹H-NMR (CDCl₃) δ: 1.59-1.65 (2H, m), 1.95-2.66 (1H, m), 3.75 (3H,s), 5.10 (2H, brs), 6.03 (1H, t), 6.69 (2H, brs), 6.82 (1H, brs),7.20-7.40 (8H, m).

[0223] MS m/z: 476 (M+1)

EXAMPLE 344-(4-Chlorophenyl)-1-[3-(6,11-dihydro-2-ethoxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol

[0224] To a solution of4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-hydroxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol (Example 32)(200 mg) in DMF (5 ml) wereadded sodium hydride (60% in oil, 25 mg), ethyl iodide (0.052 ml) andthe mixture was stiffed at room temperature for 1 hour. Water and ethylacetate were added to the reaction mixture, the organic layer wasseparated and washed with saturated aqueous sodium chloride, and driedwith magnesium sulfate. The solvent was distilled off under reducedpressure. The residue was purified by silica gel chromatography elutingwith ethyl acetate-hexane (1:1) to give the titled compound (170 mg).

[0225]¹H-NMR (CDCl₃) δ: 1.37 (3H, t), 1.60-1.65 (2H, m), 1.95-2.08 (3H,m), 2.28-75 (8H, m), 3.96 (2H, q), 5.15 (2H, brs), 6.02 (1H, t), 6.68(2H, brs), 6.82 (1H, brs), 7.19-7.42 (8H, m).

[0226] MS m/z: 490 (M+1)

EXAMPLE 351-[3-(3-Bromo-6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0227] Step 1

[0228]3-Bromo-11-(3-bromopropylidene)-6,11-dihydrodibenz[b,e]oxepine wasprepared by following the procedure of example 45, step 1 and 2, butreplacing 5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepin-5-one with3-bromo-6,11-dihydrodibenz[b,e]oxepin-11-one.

[0229]¹H-NMR (CDCl₃) δ: 2.74 (2H, q), 3.43 (2H, t), 3.77 (3H, s), 5.10(2H, brs), 6.02 (1H, t), 6.70-6.83 (3H, m), 7.21-7.38 (4H, m).

[0230] Step 2

[0231] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene withthe product of step 1.

[0232]¹H-NMR (CDCl₃) δ: 1.63-1.70 (3H, m), 1.96-2.10 (2H, m), 2.32-2.69(8H, m), 5.20 (2H, brs), 6.00 (1H, t), 6.92-7.00 (2H, m), 7.11-7.14 (1H,m), 7.24-7.42 (8H, m).

[0233] MS m/z: 524, 526 (M+1)

EXAMPLE 364-(4-Chlorophenyl)-1-[3-(6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]-4-methoxypiperidine

[0234] To a solution of4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-methoxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol(Example 2)(400 mg) in DMF (5 ml) were added sodium hydride (60% in oil,50 mg), methyl iodide (0.07 ml) and the mixture was stirred at roomtemperature for 1 hour. Water and ethyl acetate were added to thereaction mixture, the organic layer was separated and washed withsaturated aqueous sodium chloride, and dried with magnesium sulfate. Thesolvent was distilled off under reduced pressure. The residue waspurified by silica gel chromatography eluting with ethyl acetate-hexane(1:1) to give the titled compound (100 mg).

[0235]¹H-NMR (CDCl₃) δ: 1.90-2.04 (4H, m), 2.34-2.62 (8H, m), 2.93 (3H,s), 5.25 (2H, brs), 6.04 (1H, t), 6.75-6.91 (3H, m), 7.09-7.37 (9H, m).

[0236] MS m/z: 460 (M+1)

EXAMPLE 374-Acetoxy-4-(4-chlorophenyl)-1-[3-(6,11-dihydrodibenz[b,e]oxepin-11-ylidene)propyl]piperidine

[0237] To a solution of4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-methoxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-ol(Example 2)(200 mg) in dichloromethane (5 ml) were added acetyl chloride(0.06 ml), triethylamine (0.19 ml) and the mixture was stirred at roomtemperature for 1 hour. Aqueous sodium bicarbonate and ethyl acetatewere added to the reaction mixture, the organic layer was separated andwashed with saturated aqueous sodium chloride, and dried with magnesiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was purified by silica gel chromatography eluting with ethylacetate-hexane (1:4) to give the titled compound (190 mg).

[0238]¹H-NMR (CDCl₃) δ: 1.98-2.85 (12H, m), 2.02 (3H, s), 2.93 (3H, s),5.23 (2H, brs), 6.01 (1H, t), 6.73-6.90 (3H, m), 7.11-7.40 (9H, m).

[0239] MS m/z: 488 (M+1)

EXAMPLE 381-[3-(8-Bromo-4,10-dihydrothieno[3,2-c][1]benzoxepin-10-ylidene)propyl]piperidin-4-(4-chlorophenyl)-4-ol

[0240] Step 1

[0241]8-Bromo-10-(3-bromopropylidene)-4,10-dihydrothieno[3,2-c][1]benzoxepinewas prepared by following the procedure of example 45, step 1 and 2, butreplacing 5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepin-5-one with4,10-dihydrothieno[3,2-c][1]benzoxepin-10-one.

[0242]¹H-NMR (CDCl₃) d: 2.84 (2H, q), 3.45 (2H, t), 5.10 (2H, s), 6.11(1H, t), 6.65 (1H, d), 7.03-7.08 (2H, m), 7.38-7.43 (2H, m).

[0243] Step 2

[0244] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene withthe product of step 1.

[0245]¹H-NMR (CDCl₃) δ: 1.66-1.75 (3H, m), 2.03-2.16 (2H, m), 2.40-2.86(8H, m), 5.09 (0.7×2H, s), 5.14 (0.3×2H, s), 5.90 (0.3×1H, t), 6.10(0.7×1H, t), 6.64 (0.7×1H, d), 6.75 (0.3×1H, d), 6.90 (0.3×1H, d),7.03-7.09 (2H, m), 7.21-7.45 (6H, m).

[0246] MS m/z: 532 (M+1)

EXAMPLE 394-(4-Chlorophenyl)-1-[3-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]piperidin-4-ol

[0247] Step 1

[0248] 11-(3-Bromopropylidene)-6,11-dihydro-6-oxo-5H-dibenz[b,e]azepinewas prepared by following the procedure of example 45, step 1 and 2, butreplacing 5,11-dihydro-7-methoxypyrido[2,3-c][1]benzoxepin-5-one with6,11-dihydro-6-5H-dibenz[b,e]azepin-6,1 1-dione.

[0249]¹H-NMR (CDCl₃) δ: 2.70-2.92 (2H, m), 3.45 (2H, t), 5.92 (1H, t),7.08-7.58 (7H, m), 8.05 (1H, dd), 9.00 (1H, brs).

[0250] Step 2

[0251] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene withthe product of step 1.

[0252]¹H-NMR (CDCl₃) δ: 1.61-1.66 (2H, m), 1.97-2.20 (3H, m), 2.35-2.68(8H, m), 5.80 (1H, t), 7.03-7.53 (11H, m), 8.02 (1H, dd), 9.27 (1H,brs).

[0253] MS m/z: 459 (M+1)

EXAMPLE 404-(4-Chlorophenyl)-1-[3-(6,11-dihydro-5-ethyl-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]piperidin-4-ol

[0254] The titled compound was prepared by following the procedure ofexample 12, but replacing benzyl bromide with ethyl iodide.

[0255]¹H-NMR (CDCl₃) δ: 1.19-1.28 (3H, m), 1.63-1.69 (2H, m), 1.99-2.16(3H, m), 2.37-2.70 (8H, m), 3.77-3.85 (1H, m), 4.40-4.48 (1H, m), 5.85(1H, t), 7.12-7.45 (11H, m), 7.85 (1H, dd).

[0256] MS m/z: 487 (M+1)

EXAMPLE 41-1-[3-(5-n-Butyl-6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol

[0257] The titled compound was prepared by following the procedure ofexample 12, but replacing benzyl bromide with n-butyl iodide.

[0258]¹H-NMR (CDCl₃) δ: 0.90-0.98 (3H, m), 1.25-2.20 (9H, m), 2.40-2.87(8H, m), 3.62-3.72 (1H, m), 4.52-4.64 (1H, m), 5.85 (1H, t), 7.16-7.45(11H, m), 7.88 (1H, dd).

[0259] MS m/z: 515 (M+1)

EXAMPLE 424-(4-Chlorophenyl)-1-[3-(6,11-dihydro-5-(3-hydroxypropyl)-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]piperidin-4-ol

[0260] To a solution4-(4-chlorophenyl)-1-[3-(6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]piperidin-4-ol hydrochloride (Example 39)(500 mg) inDMF (8 ml) were added sodium hydride (60% in oil, 200 mg),2-(3-bromopropoxy)tetrahydro-2H-pyran (0.5 ml) and the mixture wasstirred at room temperature for 6 hours. Water and ethyl acetate wereadded to the reaction mixture, the organic layer was separated andwashed with saturated aqueous sodium chloride, and dried with magnesiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was solved in 1M hydrogen chloride in diehyl ether and stirredat room temperature for 1 hour. Aqueous sodium bicarbonate and ethylacetate were added to the reaction mixture, the organic layer wasseparated and washed with saturated aqueous sodium chloride, and driedwith magnesium sulfate. The solvent was distilled off under reducedpressure. The residue was purified by silica gel chromatography elutingwith ethyl acetate to give the titled compound (250 mg).

[0261]¹H-NMR (CDCl₃) δ: 1.25-2.87 (15H, m), 3.51-3.56 (2H, m), 3.76-3.82(1H, m), 4.81-4.87 (1H, m), 5.86 (1H, t), 7.16-7.45 (11H, m), 7.82 (1H,dd).

[0262] MS m/z: 517 (M+1)

EXAMPLE 431-[3-(5-tert-Butoxycarbonymethyl-6,11-dihydro-6-oxo-5H-dibenz[b,e]azepin-11-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol

[0263] The titled compound was prepared by following the procedure ofexample 12, but replacing benzyl bromide with tert-butyl bromoacetate.

[0264]¹H-NMR (CDCl₃) δ: 1.50 (9H, s), 1.65-1.70 (2H, m), 1.95-2.10 (3H,m), 2.42-2.75 (8H, m), 4.24 (1H, d), 4.75 (1H, d), 5.88 (1H, t),7.16-7.46 (11H, m), 7.90 (1H, dd).

[0265] MS m/z: 573 (M+1)

EXAMPLE 44 4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino [2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0266] Step 1

[0267] To a solution of the product of example 45, step 1 (4.3 g) indichloroethane (100 ml) was added boron tribromide-methyl sulfidecomplex (19.3 g) and the mixture was heated to reflux for 3 hour. Waterand ethyl acetate were added to the reaction mixture and neutralizedwith dilute NaOH solution. The organic layer was separated and washedwith saturated aqueous sodium chloride, and dried over magnesiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was purified by silica gel chromatography eluting with ethylacetate-hexane (1:2) to give5-(3-bromopropylidene)-5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b]pyridine (3.2 g).

[0268]¹H-NMR (CDCl₃) δ: 2.72 (2H, q), 3.45 (2H, t), 5.28 (2H, brs), 6.03(1H, t), 6.66-6.80 (3H, m), 7.26 (1H, dd), 7.58 (1H, dd), 8.51 (1H, dd).

[0269] Step 2

[0270] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing5-(3-bromopropylidene)-5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridine with the product of step 1.

[0271]¹H-NMR (DMSO-d₆) δ: 1.46-1.51 (2H, m), 1.74-1.85 (2H, m),2.29-2.51 (8H, m), 5.15 (2H, brs), 6.07 (1H, t), 6.61-6.70 (3H, m),7.33-7.48 (5H, m), 7.73 (1H, dd), 8.47 (1H, dd), 9.06 (1H, s).

[0272] MS m/z: 463 (M+1)

EXAMPLE 45 4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0273] Step 1

[0274] To a solution of5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one (5.0 g) in THF(50 ml) was added 1.1M cyclopropylmagnesium bromide THF solution (25 ml)at 0° C. The reaction mixture was warmed to room temperature, andstirred for 30 minutes. Aqueous ammonium chloride and ethyl acetate wereadded to the reaction mixture, the organic layer was separated andwashed with saturated aqueous sodium chloride, and dried with magnesiumsulfate. The solvent was distilled off under reduced pressure. Theresidue was filtered and washed with ethyl acetate-hexane (1:2) to give5-cyclopropyl-5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ol(5.0 g).

[0275] Step 2

[0276] To a solution of the product of step 1 (4.3 g) in acetic acid (30ml) was added 48% aqueous HBr (25 ml) at 10° C. The reaction mixture waswarmed to room temperature, and stirred for 12 hours. Water and ethylacetate were added to the reaction mixture and neutralized with diluteNaOH solution. The organic layer was separated and washed with saturatedaqueous sodium chloride, and dried over magnesium sulfate. The solventwas distilled off under reduced pressure. The residue was purified bysilica gel chromatography eluting with ethyl acetate-hexane (1:4) togive5-(3-bromopropylidene)-5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridine(5.6 g).

[0277]¹H-NMR (CDCl₃) δ: 2.74 (2H, q), 3.46 (2H, t), 3.78 (3H, s), 5.25(2H, brs), 6.07 (1H, t), 6.72-6.82 (3H, m), 7.21-7.42 (5H, m), 7.56 (1H,dd), 8.45 (1H, dd).

[0278] Step 3

[0279] To a solution the product of step 2 (1.1 g) in DMF (15 ml) wereadded 4-(4-chlorophenyl)-4-hydroxypiperidine (0.81 g) and potassiumcarbonate (0.53 g) and the mixture was stirred at room temperature for 3hours. Water and ethyl acetate were added to the reaction mixture, theorganic layer was separated and washed with saturated aqueous sodiumchloride, and dried with magnesium sulfate. The solvent was distilledoff under reduced pressure. The residue was purified by silica gelchromatography eluting with methylene chloride-methanol (10:1) to givethe titled compound as major regioisomer (0.86 g) and minor one (0.05g).

[0280] Major Isomer

[0281]¹H-NMR (CDCl₃) δ: 1.64-1.69 (2H, m), 1.91-2.08 (3H, m), 2.34-2.69(8H, m), 3.77 (3H, s), 5.25 (2H, brs), 6.07 (1H, t), 6.72-6.82 (3H, m),7.21-7.42 (5H, m), 7.56 (1H, dd), 8.45 (1H, dd).

[0282] MS m/z: 477 (M+1)

[0283] Minor Isomer

[0284]¹H-NMR (CDCl₃) δ: 1.65-1.79 (3H, m), 2.01-2.13 (2H, m), 2.35-2.76(8H, m), 3.76 (3H, s), 5.22 (2H, brs), 5.95 (1H, t), 6.72-6.80 (2H, m),7.06 (1H, d), 7.16 (1H, dd), 7.28 (2H, d), 7.42 (2H, d), 7.66 (1H, dd),8.39 (1H, dd).

[0285] MS m/z: 477 (M+1)

EXAMPLE 464-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-ethoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0286] The titled compound was prepared by following the procedure ofexample 34, but replacing4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-hydroxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-olwith4-(4-chlorophenyl)-1-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol(example 44).

[0287]¹H-NMR (CDCl₃) δ: 1.38 (3H, t), 1.67-1.72 (3H, m), 2.05-2.16 (2H,m), 2.40-2.80 (8H, m), 3.99 (2H, q), 5.26 (2H, brs), 6.05 (1H, t),6.71-6.82 (3H, m), 7.23-7.43 (5H, m), 7.57 (1H, dd), 8.47 (1H, dd).

[0288] MS m/z: 491 (M+1)

EXAMPLE 474-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-isopropoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0289] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with isopropyl bromide.

[0290]¹H-NMR (CDCl₃) δ: 1.30 (6H, d), 1.60-1.70 (3H, m), 1.99-2.09 (2H,m), 2.33-2.69 (8H, m), 4.37-4.48 (1H, m), 5.26 (2H, brs), 6.06 (1H, t),6.73-6.82 (3H, m), 7.21-7.43 (5H, m), 7.55 (1H, dd), 8.47 (1H, dd).

[0291] MS m/z: 505 (M+1)

EXAMPLE 484-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-ethoxycarbonylmethyloxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0292] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with ethyl bromoacetate.

[0293]¹H-NMR (CDCl₃) δ: 1.28 (3H, t), 1.63-1.68 (2H, m), 1.97-2.02 (3H,m), 2.33-2.68 (8H, m), 4.24 (2H, q), 4.55 (2H, s), 5.26 (2H, brs), 6.06(1H, t), 6.73-6.88 (3H, m), 7.21-7.42 (5H, m), 7.55 (1H, dd), 8.44 (1H,dd).

[0294] MS m/z: 549 (M+1)

EXAMPLE 494-(4-Chlorophenyl)-1-[3-(7-cyanomethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0295] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with bromoacetonitrile.

[0296]¹H-NMR (CDCl₃) δ: 1.62-1.67 (2H, m), 1.94-2.06 (2H, m), 2.21 (1H,brs), 2.34-2.66 (8H, m), 4.70 (2H, s), 5.26 (2H, brs), 6.10 (1H, t),6.80 (2H, brs), 6.92 (1H, brs), 7.22-7.41 (5H, m), 7.56 (1H, dd), 8.44(1H, dd).

[0297] MS m/z: 502 (M+1)

EXAMPLE 501-[3-(7-(2-Acetoxyethyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0298] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with 2-bromoethyl acetate.

[0299]¹H-NMR (CDCl₃) δ: 1.65-1.72 (3H, m), 1.97-2.09 (5H, m), 2.37-2.70(8H, m), 4.11-4.14 (2H, m), 4.37-4.41 (2H, m), 5.25 (2H, brs), 6.07 (1H,t), 6.75-6.84 (3H, m), 7.23-7.43 (5H, m), 7.56 (1H, dd), 8.47 (1H, dd).

[0300] MS m/z: 549 (M+1)

EXAMPLE 514-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-hydroxyethyl)oxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0301] To a solution of1-[3-(7-(2-acetoxyethyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol(Example 50)(140 mg) in ethanol (5 ml) were added 15% sodiun hydroxideaqueous solution (2 ml) and the mixture was heated to reflux for 1 hour.Water and ethyl acetate were added to the reaction mixture, the organiclayer was separated and washed with saturated aqueous sodium chloride,and dried with magnesium sulfate. The solvent was distilled off underreduced pressure. The residue was purified by silica gel chromatographyeluting with methylene chloride-methanol (10:1) to give the titledcompound (120 mg).

[0302]¹H-NMR (CDCl₃) δ: 1.64-1.69 (2H, m), 1.98-2.10 (3H, m), 2.36-2.79(8H, m), 3.89-3.94 (2H, m), 3.99-4.04 (2H, m), 5.24 (2H, brs), 6.04 (1H,t), 6.71-6.84 (3H, m), 7.23-7.41 (5H, m), 7.54 (1H, dd), 8.43 (1H, dd).

[0303] MS m/z: 507 (M+1)

EXAMPLE 524-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-morpholinoethyl)oxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0304] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with 4-(2-chloroethyl)morpholinehydrochloride.

[0305]¹H-NMR (CDCl₃) δ: 1.62-1.67 (2H, m), 1.95-2.08 (2H, m), 2.20-2.67(13H, m), 2.74 (2H, t), 3.67-3.71 (4H, m), 4.04 (2H, t), 5.23 (2H, brs),6.05 (1H, t), 6.73-6.82 (3H, m), 7.20-7.41 (5H, m), 7.53 (1H, dd), 8.42(1H, dd).

[0306] MS m/z: 576 (M+1)

EXAMPLE 534-(4-Chlorophenyl)-1-[3-(5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0307] Step 1

[0308] 5-(3-Bromopropylidene)-5,11-dihydro[1]benzoxepino[2,3-b]pyridinewas prepared by following the procedure of example 45, step 1 and 2, butreplacing 5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-one.

[0309]¹H-NMR (CDCl₃) δ: 2.71 (2H, q), 3.46 (2H, t), 5.33 (2H, brs), 6.04(1H, t), 7.01-7.17 (3H, m), 7.29 (1H, dd), 7.56 (1H, dd), 8.53 (1H, dd).

[0310] Step 2

[0311] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing5-(3-bromopropylidene)-5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridinewith the product of step 1.

[0312]¹H-NMR (CDCl₃) δ: 1.66-1.71 (2H, m), 2.00-2.20 (3H, m), 2.36-2.69(8H, m), 5.34 (2H, brs), 6.10 (1H, t), 6.83-6.96 (3H, m), 7.17-7.44 (6H,m), 7.60 (1H, dd), 8.46 (1H, dd).

[0313] MS m/z: 447 (M+1)

EXAMPLE 541-[3-(8-Bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0314] Step 1

[0315]8-Bromo-5-(3-bromopropylidene)-5,11-dihydro[1]benzoxepino[2,3-b]pyridinewas prepared by following the procedure of example 45, step 1 and 2, butreplacing 5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with8-bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-one.

[0316]¹H-NMR (CDCl₃) δ: 2.75 (2H, q), 3.50 (2H, t), 5.38 (2H, brs), 6.08(1H, t), 6.85-6.98 (2H, m), 7.18-7.35 (3H, m), 7.59 (1H, dd), 8.54 (1H,dd).

[0317] Step 2

[0318] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing5-(3-bromopropylidene)-5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridine with the product of step 1.

[0319]¹H-NMR (CDCl₃) δ: 1.64-1.69 (2H, m), 1.90-2.07 (3H, m), 2.30-2.67(8H, m), 5.30 (2H, brs), 6.08 (1H, t), 7.00-7.07 (2H, m), 7.13 (1H, d),7.25-7.42 (5H, m), 7.56 (1H, dd), 8.47 (1H, dd).

[0320] MS m/z: 525, 527 (M+1)

EXAMPLE 55 4-(4-Chlorophenyl)-1-[3-(10,11-dihydro-10-oxo-5H-pyrido[2,3-c][2]benzazepin-5-ylidene)propyl]piperidin-4-ol

[0321] Step 1

[0322]5-(3-Bromopropylidene)-10,11-dihydro-10-oxo-5H-pyrido[2,3-c][2]benzazepinewas prepared by following the procedure of example 45, step 1 and 2, butreplacing 5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with10,11-dihydro-5H-pyrido[2,3-c][2]benzazepin-5,1 0-dione.

[0323]¹H-NMR (CDCl₃) δ: 2.75-2.90 (2H, m), 3.45 (2H, t), 5.92 (1H, t),7.04-7.70 (5H, m), 8.10 (1H, dd), 8.48 (1H, dd), 10.00 (1H, brs).

[0324] Step 2

[0325] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing5-(3-bromopropylidene)-10,11-dihydro-5H-dibenzo[a,d]cycloheptene withthe product of step 1.

[0326]¹H-NMR (CDCl₃) δ: 1.64-1.69 (3H, m), 2.00-2.12 (2H, m), 2.35-2.70(8H, m), 5.82 (1H, t), 7.08 (1H, dd), 7.23-7.62 (8H, m), 8.04 (1H, dd),8.32 (1H, dd), 8.76 (1H, brs).

[0327] MS m/z: 460 (M+1)

EXAMPLE 564-(4-Chlorophenyl)-1-[3-(10,11-dihydro-11-methyl-10-oxo-5H-pyrido[2,3-c][2]benzazepin-5-ylidene)propyl]piperidin-4-ol

[0328] The titled compound was prepared by following the procedure ofexample 36, but replacing of4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-methoxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-olwith 5-(3-bromopropylidene)-10,11-dihydro-10-oxo-5H-pyrido[2,3-c][2]benzazepine.

[0329]¹H-NMR (CDCl₃) δ: 1.64-1.70 (3H, m), 2.00-2.10 (2H, m), 2.41-2.69(8H, m), 3.62 (3H, s), 5.82 (1H, t), 7.07 (1H, dd), 7.25-7.54 (8H, m),7.91 (1H, dd), 8.34 (1H, dd).

[0330] MS m/z: 474 (M+1)

EXAMPLE 574-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)ethyl]piperidin-4-ol

[0331] Step 1

[0332] To a solution of methyltriphenylphosphonium bromide (2.2 g) inTHF (20 ml) was added 1.6M n-butyl lithium hexane solution (2.9 ml) at0° C. for 30 minutes. To the reaction mixture cooled to 0° C. was added5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one (1.0 g)dropwise as THF solution (5 ml), and the mixture was warmed to roomtemperature, and stirred for 3 hours. Aqueous ammonium chloride andethyl acetate were added to the reaction mixture, the organic layer wasseparated and washed with saturated aqueous sodium chloride, and driedwith magnesium sulfate. The solvent was distilled off under reducedpressure. The residue was purified by silica gel chromatography elutingwith ethyl acetate-hexane (1:4) to give5,11-dihydro-7-methoxy-5-methylenepyrido[2,3-c][1]benzoxepine (0.14 g).

[0333] Step 2

[0334] To a solution of DMF (0.54 ml) was added phosphorus oxychloride(0.41 ml) at 0° C. for 10 minutes. To the reaction mixture was added theproduct of step 1 (21 0 mg) in carbontetrachloride (5 ml) and themixture was heated to reflux for 5 hours. Aqueous sodium bicarbonate andethyl acetate were added to the reaction mixture, the organic layer wasseparated and washed with saturated aqueous sodium chloride, and driedwith magnesium sulfate. The solvent was distilled off under reducedpressure. The residue was purified by silica gel chromatography elutingwith ethyl acetate-hexane (1:4) to give3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)acetaldehyde(130 mg).

[0335]¹H-NMR (CDCl₃) δ: 3.77 (0.7×3H, s), 3.79 (0.3×3H, s), 5.31 (2H,s), 6.46 (0.7×1H, d), 6.52 (0.3×1H, d), 6.78-7.40 (4H, m), 7.68 (0.3×1H,dd), 7.78 (0.7×1H, dd), 8.55 (0.7×1H, dd), 8.64 (0.3×1H, dd), 9.62(0.3×1H, d), 9.79 (0.7×1H, d).

[0336] Step 3

[0337] The titled compound was prepared by following the procedure ofexample 58, step 2, but replacing of3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propanaldehydewith product of step 2.

[0338]¹H-NMR (CDCl₃) δ: 1.64-1.82 (2H, m), 1.92-2.22 (3H, m), 2.43-2.58(2H, m), 2.79-3.45 (6H, m), 3.68 (0.3×3H, s), 3.70 (0.7×3H, s), 5.24(2H, brs), 6.18 (0.7×1H, t), 6.21 (0.3×1H, t), 6.72-7.42 (8H, m), 7.78(0.3×1H, dd), 7.85 (0.7×1H, dd), 8.42 (0.7×1H, dd), 8.46 (0.3×1H, dd).

[0339] MS m/z: 463 (M+1).

EXAMPLE 584-(4-Chlorophenyl)-1-[4-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)butyl]piperidin-4-ol

[0340] Step 1

[0341]3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propenaldehydewas prepared by following the procedure of example 57, step 2, butreplacing5,11-dihydro-7-methoxy-5-methylene[1]benzoxepino[2,3-b]pyridine with5,11-dihydro-7-methoxy-5-(propyl-1-ene) [1]benzoxepino[2,3-b]pyridine(by-product of example 45, step 3).

[0342]¹H-NMR (CDCl₃) δ: 3.78 (0.3×3H, s), 3.80 (0.7×3H, s), −5.32 (2H,brs), 6.34-6.39 (1H, m), 6.72-7.38 (6H, m), 7.58 (0.7×1H, dd), 7.77(0.3×1H, dd), 8.49 (0.3×1H, dd), 8.60 (0.7×1H, dd), 9.51 (0.7×1H, d),9.54 (0.3×1H, d).

[0343] Step 2

[0344] To a solution of the product of step 1 (90 mg) in dichloromethane(6 ml) were added sodium triacetoxyborohydride (170 mg),4-(4-chlorophenyl)-4-hydroxypiperidine (70 mg) and acetic acid (0.02 ml)and the mixture stirred at room temperature for 24 hour. Water and ethylacetate were added to the reaction mixture, the organic layer wasseparated and washed with saturated aqueous sodium chloride, and driedwith magnesium sulfate. The solvent was distilled off under reducedpressure. The residue was purified by silica gel chromatography elutingwith dichloromethane-methanol (95:5) to give4-(4-chlorophenyl)-1-[4-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)buten-2-yl]piperidin-4-ol(10 mg).

[0345]¹H-NMR (CDCl₃) δ: 1.68-1.73 (2H, m), 2.04-2.16 (2H, m), 2.43-2.72(3H, m), 2.77-2.81 (2H, m), 3.08-3.13 (2H, m), 3.73 (0.3×3H, s), 3.77(0.7×3H, s), 5.20 (2H, brs), 5.98-6.05 (1H, m), 6.23-7.43 (10H, m), 7.58(0.7×1H, dd), 7.65 (0.3×1H, dd), 8.37 (0.3×1H, dd), 8.45 (0.7×1H, dd).

[0346] MS m/z: 489 (M+1).

[0347] Step 3

[0348] To a solution of the product of step 2 (8 mg) in ethanol (2 ml)were added 10% Pd-C (2 mg) was stirred under hydrogen (under a balloon)at room temperature for 1 hour. The mixture was filtered through thecelite and distilled off under reduced pressure to give the titledcompound (6 mg).

[0349]¹H-NMR (CDCl₃) δ: 1.68-3.00 (15H, m), 3.77 (3H, s), 5.18-5.35 (2H,m), 5.94 (0.4H, t, E isomer), 6.06 (0.6H, t, Z isomer), 6.65-6.88 (3H,m), 7.05-7.73 (6H, m), 8.30-8.56 (1H, m).

[0350] MS m/z: 491 (M+1)

EXAMPLE 591-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-phenyl-4-ol

[0351] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-phenyl-4-hydroxypiperidine.

[0352]¹H-NMR (CDCl₃) δ: 1.68-1.73 (2H, m), 2.02-2.15 (3H, m), 2.38-2.72(8H, m), 3.77 (3H, s), 5.26 (2H, brs), 6.08 (1H, t), 6.72-6.83 (3H, m),7.21-7.36 (4H, m), 7.46-7.49 (2H, m), 7.58 (1H, dd), 8.46 (1H, dd).

[0353] MS m/z: 443 (M+1).

EXAMPLE 604-(4-Bromophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0354] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(4-bromophenyl)-4-hydroxypiperidine.

[0355]¹H-NMR (CDCl₃) δ: 1.65-1.69 (2H, m), 2.00-2.10 (3H, m), 2.37-2.71(8H, m), 3.76 (3H, s), 5.24 (2H, brs), 6.05 (1H, t), 6.70-6.82 (3H, m),7.24 (1H, dd), 7.38 (2H, d), 7.44 (2H, s), 7.52 (1H, dd), 8.44 (1H, dd).

[0356] MS m/z: 521,523 (M+1).

EXAMPLE 611-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0357] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-hydroxypiperidine.

[0358]¹H-NMR (CDCl₃) δ: 1.43-1.60 (2H, m), 1.80-1.98 (2H, m), 2.00-2.18(3H, m), 2.34-2.48 (4H, m), 2.63-2.76 (2H, m), 3.64-3.73 (1H, m), 3.70(3H, s), 5.35 (2H, brs), 6.06 (1H, t), 6.74-6.84 (3H, m), 7.25 (1H, dd),7.60 (1H, dd), 8.50 (1H, dd).

[0359] MS m/z: 367 (M+1).

EXAMPLE 624-Benzyl-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0360] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-benzyl-4-hydroxypiperidine.

[0361]¹H-NMR (CDCl₃) δ: 1.42-1.57 (3H, m), 1.62-1.75 (2H, m), 2.22-2.70(8H, m), 2.79 (2H, s), 3.80 (3H, s), 5.25 (2H, brs), 6.08 (1H, t),6.73-6.84 (3H, m), 7.18-7.24 (6H, m), 7.57 (1H, dd), 8.50 (1H, dd).

[0362] MS m/z: 457 (M+1).

EXAMPLE 634-Cyano-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-phenylpiperidine

[0363] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-cyano-4-phenylpiperidine.

[0364]¹H-NMR (CDCl₃) δ: 1.97-2.06 (4H, m), 2.37-2.60 (6H, m), 2.85-2.90(2H, m), 3.79 (3H, s), 5.27 (2H, brs), 6.08 (1H, t), 6.72-6.84 (3H, m),7.24-7.58 (7H, m), 8.49 (1H, dd).

[0365] MS m/z: 452 (M+1).

EXAMPLE 641-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-phenylpiperidine

[0366] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-phenylpiperidine.

[0367]¹H-NMR (CDCl₃) δ: 1.73-1.79 (4H, m), 1.96-2.03 (2H, m), 2.37-2.52(5H, m), 2.86-2.94 (2H, m), 3.77 (3H, s), 5.26 (2H, brs). 6.08 (1H, t),6.72-6.83 (3H, m), 7.17-7.31 (6H, m), 7.56 (1H, dd), 8.49 (1H, dd).

[0368] MS m/z 426 (M+1).

EXAMPLE 654-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine

[0369] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(4-chlorophenyl)piperidine.

[0370]¹H-NMR (CDCl₃) δ: 1.68-1.74 (4H, m), 1.96-2.03 (2H, m), 2.36-2.48(5H, m), 2.89-2.94 (2H, m), 3.77 (3H, s), 5.27 (2H, brs), 6.07 (1H, t),6.73-6.83 (3H, m), 7.10-7.27 (5H, m), 7.57 (1H, dd), 8.48 (1H, dd).

[0371] MS m/z: 461 (M+1).

EXAMPLE 661-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-piperidinopiperidine

[0372] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-piperidinopiperidine.

[0373]¹H-NMR (CDCl₃) δ: 1.40-2.00 (12H, m), 2.15-2.60 (9H, m), 2.80-2.92(2H, m), 3.80 (3H, s), 5.28 (2H, brs), 6.05 (1H, t), 6.75-6.86 (3H, m),7.30 (1H, dd), 7.55 (1H, dd), 8.46 (1H, dd).

[0374] MS m/z 434 (M+1).

EXAMPLE 671-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(2-keto-1-benzimidazolinyl)piperidine

[0375] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(2-keto-1-benzimidazolinyl)piperidine.

[0376]¹H-NMR (CDCl₃) δ: 1.75-1.79 (2H, m), 2.03-2.15 (2H, m), 2.38-2.52(6H, m), 2.93-2.98 (2H, m), 3.78 (3H, s), 4.30-4.38 (1H, m), 5.30 (2H,brs), 6.10 (1H, t), 6.73-6.84 (3H, m), 7.01-7.03 (3H, m), 7.21-7.28 (2H,m), 7.59 (1H, dd), 8.48 (1H, dd).

[0377] MS m/z: 483 (M+1).

EXAMPLE 681-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(2-keto-3-methyl-1-benzimidazolinyl)piperidine

[0378] The titled compound was prepared by following the procedure ofexample 36, but replacing of4-(4-chlorophenyl)-1-[3-(6,11-dihydro-2-methoxydibenz[b,e]oxepin-11-ylidene)propyl]piperidin-4-olwith1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(2-keto-1-benzimidazolinyl)piperidine.

[0379]¹H-NMR (CDCl₃) δ: 1.72-1.76 (2H, m), 2.09-2.14 (2H, m), 2.23-2.54(6H, m), 2.91-2.96 (2H, m), 3.38 (3H, s), 3.77 (3H, s), 4.30-4.37 (1H,m), 5.27 (2H, brs), 6.08 (1H, t), 6.71-6.83 (3H, m), 6.93-7.06 (3H, m),7.23-7.60 (2H, m), 8.08 (1H, dd), 8.48 (1H, dd). MS m/z: 497 (M+1).

EXAMPLE 698-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one

[0380] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 1-phenyl-1,3,8-triazaspiro[4,5]decan-4-one.

[0381]¹H-NMR (CDCl₃) δ: 1.65-1.70 (2H, m), 2.36-2.41 (2H, m), 2.53-2.79(8H, m), 3.76 (3H, s), 4.70 (2H, s), 5.25 (2H, brs), 6.10 (1H, t),6.71-6.88 (6H, m), 7.21-7.27 (3H, m), 7.58-7.61 (2H, m), 8.48 (1H, dd).

[0382] MS m/z: 497 (M+1).

EXAMPLE 704-Anilino-4-carbamyl-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine

[0383] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-anilino-4-carbamylpiperidine.

[0384]¹H-NMR (CDCl₃) δ: 1.85-1.90 (2H, m), 2.03-2.08 (2H, m), 2.19-2.46(6H, m), 2.62-2.67 (2H, m), 3.75 (3H, s), 3.97 (1H, brs), 5.27 (2H,brs), 5.53 (1H, brs), 6.03 (1H, t), 6.60 (2H, d), 6.70-6.85 (4H, m),7.12-7.25 (4H, m), 7.53 (1H, dd), 8.46 (1H, dd).

[0385] MS m/z 485 (M+1).

EXAMPLE 711-(4-Chlorophenyl)-4-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperazine

[0386] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 1-(4-chlorophenyl)piperazine.

[0387]¹H-NMR (CDCl₃) δ: 2.36-2.53 (8H, m), 3.07-3.09 (4H, m), 3.76 (3H,s), 5.26 (2H, brs), 6.08 (1H, t), 6.72-6.81 (5H, m), 7.16-7.28 (3H, m),7.56 (1H, dd), 8.49 (1H, dd).

[0388] MS m/z: 462 (M+1).

EXAMPLE 721-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(2-pyrimidyl)piperazine

[0389] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 1-(2-pyrimidyl)piperazine.

[0390]¹H-NMR (CDCl₃) δ: 2.37-2.53 (8H, m), 3.74-3.83 (7H, m), 5.27 (2H,brs), 6.08 (1H, t), 6.45 (1H, t), 6.72-6.83 (3H, m), 7.25 (1H, dd), 7.56(1H, dd), 8.27 (2H, d), 8.49 (1H, dd).

[0391] MS m/z: 430 (M+1).

EXAMPLE 731-Cyclohexyl-4-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperazine

[0392] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 1-cyclohexylpiperazine.

[0393]¹H-NMR (CDCl₃) δ: 1.12-1.27 (6H, m), 1.74-1.86 (6H, m), 2.18-2.52(11H, m), 3.76 (3H, s), 5.26 (2H, brs), 6.04 (1H, t), 6.74-6.81 (3H, m),7.23 (1H, dd), 7.55 (1H, dd), 8.48 (1H, dd).

[0394] MS m/z: 434 (M+1).

EXAMPLE 741-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(2-furoyl)piperazine

[0395] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 1-(2-furoyl)piperazine.

[0396]¹H-NMR (CDCl₃) δ: 2.34-2.48 (8H, m), 3.71-3.74 (7H, s), 5.24 (2H,brs), 6.05 (1H, t), 6.42 (1H, dd), 6.70-6.80 (3H, m), 6.93 (1H, d), 7.23(1H, dd), 7.42 (1H, d), 7.53 (1H, dd), 8.46 (1H, dd).

[0397] MS m/z: 446 (M+1).

Example 75cl4-(3-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0398] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(3-chlorophenyl)-4-hydroxypiperidine.

[0399]¹H-NMR (CDCl₃) δ: 1.61-1.75 (2H, m), 1.98 (1H, brs), 1.99 (2H,dt), 2.25 (3H, s), 2.30-2.76 (8H, m), 3.73 (3H, s), 5.22 (2H, brs), 5.95(0.1H, t, E isomer), 6.04 (0.9H, t, Z isomer), 6.71-6.89 (3H, m), 6.95(1H, dd), 7.15-7.20 (0.3H, m, E isomer), 7.21-7.35 (2.7H, m, Z isomer),7.53 (0.9H, dd, Z isomer), 7.65 (0.1H, dd, E isomer), 8.35 (0.1H, dd, Eisomer), 8.45 (0.9H, dd, Z isomer).

[0400] MS m/z: 477 (M+1)

EXAMPLE 764-(2-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0401] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(2-chlorophenyl)-4-hydroxypiperidine.

[0402]¹H-NMR (CDCl₃) δ: 1.98-2.08 (2H, m), 2.24 (2H, dt), 2.38-2.78 (9H,m), 3.77 (3H, s), 5.27 (2H, brs), 6.08 (1H, t), 6.82-6.75 (3H, m),7.28-7.19 (3H, m), 7.33 (1H, dd), 7.49 (1H, dd), 7.58 (1H, dd), 8.40(0.1H, dd, Z isomer), 8.47 (0.9H, dd, E isomer).

[0403] MS m/z: 477 (M+1)

EXAMPLE 771-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-fluorophenyl)piperidin-4-ol

[0404] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(4-fluorophenyl)-4-hydroxypiperidine.

[0405]¹H-NMR (CDCl₃) δ: 1.58-1.72 (2H, m), 2.04 (2H, dt), 2.22-2.78 (9H,m), 3.75 (3H, s), 5.26 (2H, brs), 6.09 (1H, t), 6.70-6.88 (3H, m), 7.00(2H, dd), 7.23 (1H, dd), 7.42 (2H, dd), 7.56 (1H, dd), 8.41 (1H, dd).

[0406] MS m/z: 461 (M+1)

EXAMPLE 781-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(p-tolyl)piperidin-4-ol

[0407] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(p-tolyl)-4-hydroxypiperidine.

[0408]¹H-NMR (CDCl₃) δ: 1.65-1.78 (2H, m), 2.02 (2H, dt), 2.31 (3H, s),2.24-2.75 (9H, m), 3.75 (3H, s), 5.25 (2H, brs), 6.07 (1H, t), 6.72-6.84(3H, m), 7.13 (2H, d), 7.23 (1H, dd), 7.34 (1H, d), 7.56 (1H, dd), 8.43(1H, dd).

[0409] MS m/z: 457 (M+1)

EXAMPLE 794-(3,4-Dichlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0410] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(3,4-dichlorophenyl)-4-hydroxypiperidine.

[0411]¹H-NMR (CDCl₃) δ: 1.58-1.72 (2H, m), 1.84 (1H, brs), 2.02 (2H,td), 2.32-2.72 (8H, m), 3.76 (3H, s), 5.27 (2H, brs), 5.95 (0. 1H, t, Eisomer), 6.07 (0.9H, t, Z isomer), 6.72-6.85 (3H, M), 7.12-7.20 (0.2H,m, E isomer), 7.21-7.32 (0.18H, m, Z isomer), 7.32-7.45 (1H, m),7.52-7.56 (2H, m), 8.37 (0.9H, dd, E siomer), 8.45 (0.1H, dd, Z isomer).

[0412] MS m/z: 512 (M+1)

EXAMPLE 834-(5-Chloropyridin-2-yl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0413] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(5-chloropyridin-2-yl)-4-hydroxypiperidine.

[0414]¹H-NMR (CDCl₃) δ: 1.77-1.82 (2H, m), 2.36-2.94 (11H, m), 3.77 (3H,brs), 5.26 (2H, brs), 6.07 (1H, t), 6.76-6.84 (3H, m), 7.26 (1H, dd),7.57 (1H, dd), 8.49-7.48 (1H, d), 8.42-8.53 (3H, m).

[0415] MS m/z: 478 (M+1)

EXAMPLE 854-(5-Chloro-2-keto-1-benzimidazolinyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine

[0416] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(5-chloro-2-keto-1-benzimidazolinyl)piperidine.

[0417]¹H-NMR (CDCl₃) δ: 1.68-1.72 (2H, m), 2.03-2.60 (8H, m), 2.90-3.02(2H, m), 3.78 (3H, s), 4.32-4.21 (1H, m), 5.29 (2H, brs), 5.95 (0.1H, t,E siomer), 6.08 (0.9H, t, Z isomer), 6.70-6.92 (3H, m), 7.02 (1H, dd),7.08-7.20 (1H, m), 7.26 (1H, dd), 7.58 (0.9H, dd, Z isomer), 7.70 (0.1H,dd, E isomer), 8.42 (0.1H, dd, E isomer), 8.48 (0.9H, dd, Z isomer),10.5 (1H, s). (NH is not observed in the spectrum)

[0418] MS m/z: 517 (M+1)

EXAMPLE 864-(p-Chloroanilino)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine

[0419] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(p-chloroanilino)piperidine.

[0420]¹H-NMR (CDCl₃) δ: 1.20-1.54 (2H, m), 1.85-2.20 (4H, m), 2.24-2.60(4H, m), 2.73 (2H, m), 3.18 (1H, m), 3.77 (3H, s), 5.27 (2H, brs), 6.06(1H, t), 6.47 (2H, m), 6.68-6.90 (3H, m), 7.07 (2H, m), 7.24 (1H, dd),7.57 (1H, m), 8.48 (1H, dd). NH signal was not observed.

[0421] MS m/z: 476 (M+1)

EXAMPLE 891-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(p-tosyl)piperazine

[0422] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 1-(p-tosyl)piperazine.

[0423]¹H-NMR (CDCl₃) δ: 2.20-2.54 (11H, m), 2.82-3.10 (4H, m), 3.73 (3H,s), 5.16 (2H, brs), 6.00 (1H, t), 6.66-6.85 (3H, m), 7.21 (1H, dd), 7.31(2H, m), 7.51 (1H, dd), 7.61 (2H, m), 8.45 (1H, dd).

[0424] MS m/z: 506 (M+1)

EXAMPLE 901′-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]spiro[isobenzofuran-1(3H), 4′-piperidine]

[0425] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith spiro[isobenzofuran-1 (3H), 4′-piperidine].

[0426]¹H-NMR (CDCl₃) δ: 1.62-1.82 (2H, m), 1.92 (2H, dt), 2.25-2.85 (8H,m), 3.76 (3H, s), 5.03 (2H, s), 5.30 (2H, brs), 6.11 (1H, t), 6.68-6.90(3H, m), 7.02-7.34 (5H, m), 7.58 (1H, dd), 8.48 (1H, dd).

[0427] MS m/z: 455 (M+1)

EXAMPLE 915-Chloro-1′-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]spiro[isobenzofuran-1(3H), 4′-piperidine]

[0428] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 5-chlorospiro[isobenzofuran-1(3H), 4′-piperidine].

[0429]¹H-NMR (CDCl₃) δ: 1.69-1.74 (2H, m), 1.81-1.93 (2H, m), 2.30-2.44(4H, m), 2.52-2.63 (2H, m), 2.71-2.75 (2H, m), 3.79 (3H, s), 5.00 (2H,s), 5.28 (2H, brs), 6.09 (1H, t), 6.73-6.84 (3H, m), 7.03 (1H, d), 7.17-7.28 (3H, m), 7.58 (1H, dd), 8.49 (1H, dd).

[0430] MS m/z: 489 (M+1)

EXAMPLE 1114-(4-Chlorophenyl)-1-[3-(5,11-dihydro[1]benzothiepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0431] The titled compound was prepared by following the procedure ofexample 45, but replacing5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with5,11-dihydro[1]benzothiepino[2,3-b]pyridin-5-one.

[0432]¹H-NMR (CDCl₃) δ: 1.66-1.78 (3H, m), 2.04-2.65 (1 OH, m), 3.66(1H, brd), 5.05 (1H, brd), 6.03 (1H, t), 7.04-7.46 (10H, m), 8.44 (1H,dd).

[0433] MS m/z: 463 (M+1)

EXAMPLE 1144-(4-Chlorophenyl)-11-[3-(5,11-dihydro-8-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0434] The titled compound was prepared by following the procedure ofexample 45, but replacing5,11-dihydro-7-methoxy[11]benzoxepino[2,3-b]pyridin-5-one with5,11-dihydro-8-methoxy[1]benzoxepino[2,3-b]pyridin-5-one.

[0435]¹H-NMR (CDCl₃) δ: 1.66-1.70 (3H, m), 1.98-2.09 (2H, m), 2.34-2.70(8H, m), 3.75 (3H, s), 5.32 (2H, brs), 6.02 (1H, t), 6.39 (1H, d), 6.51(1H, dd), 7.19-7.44 (6H, m), 7.57 (1H, dd), 8.49 (1H, dd).

[0436] MS m/z: 477 (M+1)

EXAMPLE 1154-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0437] The titled compound was prepared by following the procedure ofexample 45, but replacing5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with5,11-dihydro-7-methyl[1]benzoxepino[2,3-b]pyridin-5-one.

[0438]¹H-NMR (CDCl₃) δ: 1.50 (1H, brs), 1.66-1.70 (2H, m), 1.98-2.10(2H, m), 2.28 (3H, s), 2.34-2.42 (4H, m), 2.52-2.57 (2H, m), 2.66-2.70(2H, m), 5.30 (2H, brs), 6.08 (1H, t), 6.76 (1H, d), 6.97 (1H, dd), 7.09(1H, d), 7.24-7.44 (5H, m), 7.57 (1H, dd), 8.49 (1H, dd).

[0439] MS m/z: 461 (M+1)

EXAMPLE 1171-[3-(7-Chloro-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0440] The titled compound was prepared by following the procedure ofexample 45, but replacing5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with7-chloro-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-one.

[0441]¹H-NMR (CDCl₃) δ: 1.66-1.71 (3H, m), 2.00-2.10 (2H, m), 2.36-2.44(4H, m), 2.52-2.57 (2H, m), 2.66-2.70 (2H, m), 5.32 (2H, brs), 6.13 (1H,t), 6.78 (1H, d), 7.11 (1H, dd), 7.26-7.44 (5H, m), 7.58 (1H, dd), 8.51(1H, dd).

[0442] MS m/z: 481 (M+1)

EXAMPLE 1181-[3-(7-Carboxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0443] A mixture of the product of example 169 (500 mg), potassiumacetate (330 mg), palladium(II) diacetate (10 mg),1,1′-bis(diphenylphosphino)ferrocene (93 mg), in dimethylsulfoxide (10ml) was purged with carbon monoxide for 5 minutes and stirred under acarbon monoxide balloon at 60° C. for 3 hours. Water was added to thereaction mixture, the precipitation was filtered. The solid weredissolved with ethyl acetate and dilute sodium hydroxide solution. Theaqueous layer was separated and neutralized with dilute hydrochloricacid. The precipitation was filtered to give the titled compound (250mg).

[0444]¹H-NMR (DMSO-d₆) δ: 1.45-1.55 (2H, m), 1.75-1.85 (2H, m),2.36-2.62 (8H, m), 5.42 (2H, brs), 6.21 (1H, t), 6.90 (1H, d), 7.40-7.52(5H, m), 7.75 (1H, dd), 7.83 (1H, dd), 7.95 (1H, d), 8.56 (1H, dd).

[0445] MS m/z: 491 (M+1)

Example 1204-(4-Chlorophenyl)-1-[3-(7-carboxymethyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0446] To a solution of product of Example 290 (3.7 g) in methanol (74ml), acetic acid (6 ml), and water (37 ml) were added sodium periodate(1.7 g) in water (1 5 ml) at 0° C., and the mixture was stirred at roomtemperature for 1 hour. To the reaction mixture were added amidosulfuricacid (1.2 g) and sodium chlorite (0.89 g) in water (10 ml), and themixture was stirred at room temperature for 15 minutes. The reactionmixture was distilled off under reduced pressure into half volume. Theresidue was neutralized with 1N sodium hydroxide. The precipitation wasfiltered and washed with water to give the titled compound (2.6 g).

[0447]¹H-NMR (DMSO-d₆) δ: 1.45-1.50 (2H, m), 1.73-1.82 (2H, m),2.24-2.50 (8H, m), 3.50 (2H, s), 4.84 (1H, brs), 5.24 (2H, brs), 6.13(1H, t), 6.74 (1H, d), 7.06 (1H, dd), 7.21 (1H, d), 7.33-7.48 (5H, m),7.74 (1H, dd), 8.50 (1H, dd).

EXAMPLE 1224-(4-Chlorophenyl)-1-[3-(7-dimethylaminocarbonylmethyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0448] The titled compound was prepared by following the procedure ofexample 134, but replacing the product of example 133 with the productof example 120.

[0449]¹H-NMR (CDCl₃) δ: 1.65-1.70 (2H, m), 1.95-2.06 (2H, m), 2.31-2.66(9H, m), 2.93 (3H, s), 3.00 (3H, s), 3.61 (2H, s), 5.29 (2H, brs), 6.09(1H, t), 6.78 (1H, d), 7.00 (1H, dd), 7.20-7.43 (6H, m), 7.56 (1H, dd),8.42 (1H, dd).

[0450] MS m/z: 532 (M+1)

EXAMPLE 1231-[3-(7-(2-Carboxy)ethyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol

[0451] The titled compound was prepared by following the procedure ofexample 133, but replacing the product of example 48 with the product ofexample 288. 1

[0452]¹H-NMR (DMSO-d₆) δ: 1.44-1.49 (2H, m), 1.70-1.82 (2H, m),2.22-2.48 (10H, m), 2.75 (2H, t), 4.82 (1H, brs), 5.23 (2H, brs), 6.14(1H, t), 6.71 (1H, d), 7.04 (1H, dd), 7.17 (1H, d), 7.33-7.48 (5H, m),7.72 (1H, dd), 8.49 (1H, dd).

[0453] MS m/z: 519 (M+1)

EXAMPLE 1284-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-propoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0454] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with propyl iodide.

[0455]¹H-NMR (CDCl₃) δ: 1.03 (3H, t), 1.65-1.70 (2H, m), 1.78 (2H, q),1.98-2.09 (3H, m), 2.37-2.45 (4H, m), 2.51-2.56 (2H, m), 2.66-2.70 (2H,m), 3.88 (2H, t), 5.26 (2H, brs), 6.08 (1H, t), 6.72-6.84 (3H, m),7.23-7.43 (5H, m), 7.58 (1H, dd), 8.43 (1H, dd).

[0456] MS m/z: 505 (M+1)

EXAMPLE 1304-(4-Chlorophenyl)-1-[3-(7-cyclopropylmethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0457] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with cyclopropylmethyl bromide.

[0458]¹H-NMR (CDCl₃) δ: 0.31-0.37 (2H, m), 0.60-0.67 (2H, m), 1.21-1.28(1H, m), 1.66-1.72 (3H, m), 2.01-2.11 (2H, m), 2.37-2.71 (8H, m), 3.77(2H, d), 5.27 (2H, brs), 6.08 (1H, t), 6.73-6.86 (3H, m), 7.23-7.44 (5H,m), 7.58 (1H, dd), 8.47 (1H, dd).

[0459] MS m/z: 517 (M+1)

EXAMPLE 1314-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-dimetylaminoethyl)oxy)[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0460] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with 2-(dimethylamino)ethylchloride hydrochloride.

[0461]¹H-NMR (CDCl₃) δ: 1.71-1.76 (2H, m), 2.12-2.21 (2H, m), 2.38 (6H,s), 2.40-2.79 (11H, m), 4.07 (2H, t), 5.28 (2H, brs), 6.07 (1H, t),6.74-6.86 (3H, m), 7.27-7.46 (5H, m), 7.59 (1H, dd), 8.49 (1H, dd).

[0462] MS m/z: 534 (M+1)

EXAMPLE 1324-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(tetrazol-5-yl)methyloxy)[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0463] Step 1

[0464]4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-triphenylmethyltetrazol-5-yl)methyloxy)[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol was preparedby following the procedure of example 46, but replacing ethyl iodidewith (2-triphenylmethyltetrazol-5-yl)methyl chloride.

[0465]¹H-NMR (CDCl₃) δ: 1.64-1.70 (3H, m), 2.02-2.15 (2H, m), 2.35-2.71(8H, m), 5.29 (2H, brs), 5.33 (2H, s), 6.03 (1H, t), 6.77 (1H, d), 6.83(1H, dd), 6.96 (1H, d), 7.04-7.08 (6H, m), 7.23-7.45 (14H, m), 7.54 (1H,dd), 8.50 (1H, dd).

[0466] Step 2

[0467] A solution of the product of step 1 (530 mg) in acetone (2.5 ml),acetic acid (2.5 ml) and water (2.5 ml) was stirred at 55° C. for 30minutes. The reaction mixture was distilled off under reduced pressure.The residue was washed with methanol to give the titled compound (280mg).

[0468]¹H-NMR(DMSO-d₆) δ: 1.69-1.74 (2H, m), 1.99-2.09 (2H, m), 2.95-3.14(8H, m), 5.18 (2H, brs), 5.20 (2H, s), 6.14 (1H, t), 6.76 (1H, d), 6.93(1H, dd), 7.04 (1H, d), 7.39-7.48 (5H, m), 7.78 (1H, dd), 8.52 (1H, dd).

[0469] MS m/z: 545 (M+1)

EXAMPLE 1331-[3-(7-Carboxymethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0470] To a solution of product of example 48 (3.0 g) in methanol (50ml) was added 1N sodium hydroxide solution (8 ml) and the mixturestirred at room temperature for 1 hour. The reaction mixture wasdistilled off under reduced pressure. The residue was dissolved withwater and neutralized with 1N hydrochloric acid. The precipitation wasfiltered and washed with water to give the titled compound (2.6 g).

[0471]¹H-NMR (DMSO-d₆) δ: 1.48-1.53 (2H, m), 1.76-1.88 (2H, m),2.32-2.60 (8H, m), 4.60 (2H, s), 5.18 (2H, brs), 6.16 (1H, t), 6.72-6.84(3H, m), 7.34-7.48 (5H, m), 7.73 (1H, dd), 8.50 (1H, dd).

[0472] MS m/z: 521 (M+1)

EXAMPLE 1344-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-dimethylaminocarbonylmethyloxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0473] To a solution of product of example 133 (420 mg) indimethylformamide (17 ml) were added 1-hydroxybenzotriazol hydrate (250mg), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (310mg), dimethylamine hydrochloride (270 mg) and triethylamine (0.45 ml),and the mixture stirred at room temperature for 12 hours. Water andchloroform were added to the reaction mixture, the organic layer wasseparated and washed with saturated aqueous sodium chloride, and driedwith magnesium sulfate. The solvent was distilled off under reducedpressure to give the titled compound (380 mg).

[0474]¹H-NMR (CDCl₃) δ: 1.67-1.71 (2H, m), 1.95-2.11 (3H, m), 2.37-2.71(8H, m), 2.97 (3H, s), 3.08 (3H, s), 4.64 (2H, s), 5.27 (2H, brs), 6.09(1H, t), 6.74-6.82 (2H, m), 6.93 (1H, d), 7.24-7.44 (5H, m), 7.58 (1H,dd), 8.47 (1H, dd).

[0475] MS m/z: 548 (M+1)

EXAMPLE 1354-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-morpholinocarbonylmethyloxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0476] The titled compound was prepared by following the procedure ofexample 134, but replacing dimethylamine hydrochloride with morpholine.

[0477]¹H-NMR (CDCl₃): 1.67-1.71 (2H, m), 1.87 (1H, brs), 2.00-2.11 (2H,m), 2.38-2.71 (8H, m), 3.61-3.68 (8H, m), 4.65 (2H, s), 5.27 (2H, brs),6.09 (1H, t), 6.74-6.83 (2H, m), 6.90 (1H, d), 7.25-7.44 (5H, m), 7.58(1H, dd), 8.48 (1H, dd).

[0478] MS m/z: 590 (M+1)

EXAMPLE 1384-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-ethoxycarbonyl-1-methylethyl)oxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0479] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with ethyl 2-bromoisobutylate.

[0480]¹H-NMR (CDCl₃) δ: 1.27 (3H, t), 1.56 (6H, s), 1.63-1.71 (3H, m),2.01-2.10 (2H, m), 2.35-2.70 (8H, m), 4.24 (2H, q), 5.28 (2H, brs), 6.05(1H, t), 6.67-6.75 (2H, m), 6.87 (1H, d), 7.24-7.44 (5H, m), 7.56 (1H,dd), 8.49 (1H, dd).

[0481] MS m/z: 577 (M+1)

EXAMPLE 1391-[3-(7-(1-Carboxy-1-methylethyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0482] The titled compound was prepared by following the procedure ofexample 133, but replacing product of example 48 with product of example138.

[0483]¹H-NMR (DMSO-d₆) δ: 1.45-1.52 (8H, m), 1.79-1.85 (2H, m),2.28-2.53 (8H, m), 5.19 (2H, brs), 6.07 (1H, t), 6.69-6.73 (2H, m), 6.85(1H, d), 7.33-7.47 (5H, m), 7.71 (1H, dd), 8.48 (1H, dd).

[0484] MS m/z: 549 (M+1)

EXAMPLE 1401-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-methoxyphenyl)piperidin-4-ol

[0485] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(4-methoxyphenyl)-4-hydroxypiperidine.

[0486]¹H-NMR (CDCl₃) δ: 1.62-1.75 (2H, m), 2.08 (2H, dt), 2.41-2.76 (9H,m), 3.77 (3H, s), 3.78 (3H, s), 5.26 (2H, brs), 6.06 (1H, t), 6.75-6.871(5H, m), 7.23 (1H, dd), 7.38 (2H, d), 7.57 (1H, dd), 8.45 (1H, dd).

[0487] MS m/z: 473 (M+1)

EXAMPLE 1414-(4-Cyanophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0488] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(4-cyanophenyl)-4-hydroxypiperidine.

[0489]¹H-NMR (CDCl₃) δ: 1.58-1.70 (2H, m), 2.03 (2H, t), 2.31-2.64 (7H,m), 2.65-2.78 (2H, m), 3.75 (3H, s), 5.26 (2H, brs), 5.95 (0.1H, t, Eisomer), 6.05 (0.9H, t, Z isomer), 6.70-6.80 (3H, m), 7.22 (1H, dd),7.54-7.68 (5H, m), 8.31 (0.1H, dd, E iosmer), 8.39 (0.9H, dd, Z isomer).

[0490] MS m/z:468 (M+1)

EXAMPLE 1421-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-hydroxyphenyl)piperidin-4-ol

[0491] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(4-hydroxyphenyl)-4-hydroxypiperidine.

[0492]¹HNMR (CDCl₃) δ: 1.76-1.88 (2H, m). 2.08-2.22 (2H, m), 2.45-2.95(9H, m), 3.76 (3H, s), 5.28 (2H, brs), 5.95 (0.3H, t, E isomer), 6.04(0.7H, t, Z iosmer), 6.69-6.72 (3H, m), 6.90 (2H, d), 7.20-7.30 (3H, m),7.56 (0.7H, dd, Z isomer), 7.67 (0.3H, dd, E isomer), 8.46 (0.7H, dd, Zisomer), 8.47 (0.3H, dd, E isomer). OH signal was not observed.

[0493] MS m/z: 473 (M+1)

EXAMPLE 1431-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-fluoro-3-methylphenyl)piperidin-4-ol

[0494] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(4-fluoro-3-methylphenyl)-4-hydroxypiperidine.

[0495]¹H-NMR (CDCl₃) δ: 1.62-1.75 (2H, m), 2.05 (1H, brs), 2.09 (2H,dt), 2.25 (3H, s), 2.30-2.76 (8H, m), 3.76 (3H, s), 5.26 (2H, brs), 5.96(0.1H, t, E isomer), 6.07 (0.9H, t, Z isomer), 6.75-6.89 (3H, m), 6.93(1H, t), 7.11-7.20 (0.3H, m, E isomer), 7.21-7.35 (0.24H, m, Z isomer),7.56 (0.9H, dd, E isomer), 7.67 (0.1H, dd, E isomer), 8.38 (0.1H, dd, Eisomer), 8.45 (0.9H, dd, Z isomer).

[0496] MS m/z: 475 (M+1)

EXAMPLE 1444-(3,4-difluorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0497] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(3,4-difluorophenyl)-4-hydroxypiperidine.

[0498]¹H-NMR (CDCl₃) δ: 1.58-1.72 (2H, m), 1.96 (2H, dt), 2.33-2.71 (8H,m), 3.73 (3H, s), 5.23 (2H, brs), 5.94 (0.1H, t, E isomer), 6.04 (0.9H,t, Z isomer), 8.38-8.36 (0.9H, m, Z isomer), 6.68-6.79 (3H, m),6.98-7.38 (4H, m), 7.50-7.62 (0.9H, m, Z isomer), 7.63-7.68 (0.1H, m, Eisomer), 8.29-8.32 (0.1H, m, E isomer), 8.32-8.44 (0.9H, m, Z isomer).OH signal was not observed.

[0499] MS m/z: 479 (M+1)

EXAMPLE 1454-(4-Chloro-3-trifuluoromethylphenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0500] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(4-chloro-3trifluoromethylphenyl)-4-hydroxypiperidine.

[0501]¹H-NMR (CDCl₃) δ: 1.62-1.74 (2H, m), 2.10 (2H, dt), 2.35-2.80 (8H,m), 2.42 (1H, brs), 3.76 (3H, s), 5.26 (2H, brs), 6.07 (0.9H, t, Zisomer), 6.03 (0.1H, t, E isomer), 6.82-6.71 (3H, m), 7.24 (1H, dd),7.43 (1H, d), 7.56 (1.8H, dd, Z isomer), 7.65 (0.2H, dd, E isomer) 7.83(1H, d), 8.36 (0.1H, dd, E isomer), 8.44 (0.9H, dd, Z iosmer),

[0502] MS m/z: 545 (M+1)

EXAMPLE 1464-(3,5-dichlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0503] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(3,5-dichlorophenyl)-4-hydroxypiperidine.

[0504]¹H-NMR (CDCl₃) δ: 1.58-2.22 (5H, m), 2.38-2.77 (8H, m), 3.76 (3H,s), 5.26 (2H, brs), 5.92 (0.1H, t, E isomer), 6.07 (0.9H, t, Z isomer),6.83-6.71 (3H, m), 7.19-7.42 (4H, m), 7.56 (0.9H, dd, Z isomer), 7.68(0.1H, dd, E isomer), 8.38 (0.1H, dd, E isomer), 8.45 (0.9H, dd, Zisomer).

[0505] MS m/z: 512 (M+1)

EXAMPLE 1471-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(2-pyridyl)piperidin-4-ol

[0506] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(2-pyridyl)-4-hydroxypiperidine

[0507]¹H-NMR (CDCl₃) δ: 1.54-1.65 (2H, m), 2.06 (2H, dt), 2.07 (1H,brs), 2.35-2.62 (7H, m), 2.73-2.87 (2H, m), 3.78 (3H, s), 5.28 (2H,brs), 6.08 (1H, t), 6.72-6.85 (3H, m), 7.14-7.29 (2H, m), 7.57 (1H, d),7.70 (1H, dd), 8.48 (2H, dd).

[0508] MS m/z: 444 (M+1)

EXAMPLE 1481-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(3-pyridyl)piperidin-4-ol

[0509] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(3-pyridyl)-4-hydroxypiperidine.

[0510]¹H-NMR (CDCl₃) δ: 1.65-1.78 (2H, m), 2.08 (2H, dt), 2.37-2.88 (7H,m), 2.63-2.79 (2H, m), 3.78 (3H, s), 5.28 (2H, brs), 6.02 (0.1H, t, Eisomer), 6.07 (0.9H, t, Z isomer), 6.70-6.84 (3H, m), 7.22-7.32 (3H, m),7.56 (1H, dd), 7.77 (1H, dd), 8.46 (0.9H, d), 8.57 (0.1H, dd, E isomer),8.73 (1H, dd).

[0511] MS m/z: 444 (M+1)

EXAMPLE 1491-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-pyridyl)piperidin-4-ol

[0512] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(4-pyridyl)-4-hydroxypiperidine.

[0513]¹H-NMR (CDCl₃) δ: 1.58-1.72 (2H, m), 2.03 (2H, dt), 2.34-2.89 (8H,m), 2.96 (1H, brs), 3.76 (3H, s), 5.25 (2H, brs), 6.06 (1H, t),6.72-6.83 (3H, m), 7.24 (1H, dd), 7.37 (2H, dd), 7.56 (1H, dd), 8.45(1H, dd), 8.48 (2H, dd).

[0514] MS m/z: 444 (M+1)

EXAMPLE 1501-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-trifluoromethylphenyl)piperidin-4-ol

[0515] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(4-trifluoromethylphenyl)-4-hydroxypiperidine.

[0516]¹H-NMR (CDCl₃) δ: 1.64-1.75 (2H, m), 2.01 (1H, brs), 2.16 (2H,dt), 2.38-2.86 (8H, m), 3.76 (3H, s), 5.26 (2H, brs), 6.04 (1H, t),6.72-6.84 (3H, m), 7.23 (1H, dd), 7.56 (5H, m), 8.42 (1H, dd).

[0517] MS m/z: 511 (M+1)

EXAMPLE 1514-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine

[0518] The titled compound was prepared by following the procedure ofexample 44, step 2, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(4-chlorophenyl)piperidine.

[0519]¹H-NMR (CDCl₃) δ: 1.62-1.92 (4H, m), 1.94-2.18 (2H, m), 2.28-2.64(5H, m), 2.99 (2H, m), 5.25 (2H, brs), 6.00 (1H, t), 6.60-6.82 (3H, m),7.02-7.36 (5H, m), 7.50 (1H, dd), 8.47 (1H, dd). OH signal was notobserved.

[0520] MS m/z: 447 (M+1)

EXAMPLE 1524-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-ethoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine

[0521] The titled compound was prepared by following the procedure ofexample 46, but replacing the product of example 44 with the product ofexample 151.

[0522]¹H-NMR (CDCl₃) δ:1.40 (3H, t), 1.52-2.14 (6H, m), 2.30-2.57 (5H,m), 2.94 (2H, m), 4.00 (2H, q), 5.28 (2H, brs), 6.07 (1H, t), 6.68-6.86(3H, m), 7.05-7.36 (5H, m), 7.58 (1H, m), 8.49 (1H, m).

[0523] MS m/z: 475 (M+1)

EXAMPLE 1534-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-ethoxycarbonylmethyloxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine

[0524] The titled compound was prepared by following the procedure ofexample 48, but replacing the product of example 44 with the product ofexample 151.

[0525]¹H-NMR (CDCl₃) δ: 1.29 (3H, t), 1.56-1.85 (4H, m), 1.99 (2H, dt),2.28-2.55 (5H, m), 2.91 (2H, m), 4.27 (2H, q), 4.58 (2H, s), 5.28 (2H,brs), 6.09 (1H, t), 6.68-6.95 (3H, m), 7.07-7.32 (5H, m), 7.58 (1H, dd),8.49 (1H, dd).

[0526] MS m/z: 533 (M+1)

EXAMPLE 1541-[3-(7-(Carboxymethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidine

[0527] The titled compound was prepared by following the procedure ofexample 133, but replacing the product of example 48 with the product ofexample 153.

[0528]¹H-NMR (CD₃OD) δ: 1.82-2.17 (4H, m), 2.69 (2H, m), 2.86 (1H, m),3.07 (2H, m), 3.30 (2H, m), 3.57 (2H, m), 4.57 (2H, s), 5.21 (2H, brs),6.10 (1H, t), 6.70-7.04 (3H, m), 7.16-7.38 (4H, m), 7.44 (1H, m), 7.77(1H, m), 8.47 (1H, m). COOH signal was not observed.

[0529] MS m/z: 505 (M+1)

EXAMPLE 1554-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-dimethylaminocarbonylmethyloxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine

[0530] The titled compound was prepared by following the procedure ofexample 134, but replacing the product of example 133 with the productof example 154.

[0531]¹H-NMR (CDCl₃) δ: 1.58-1.92 (4H, m), 2.04 (2H, m), 2.30-2.68 (5H,m), 2.93 (2H, m), 2.98 (3H, s), 3.08 (3H, s), 4.65 (2H, s), 5.28 (2H,brs), 6.07 (1H, t), 6.70-6.98 (3H, m), 7.08-7.36 (5H, m), 7.60 (1H, m),8.50 (1H, m).

[0532] MS m/z: 532 (M+1)

EXAMPLE 1561-[3-(7-(2-Acetoxyethyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine

[0533] The titled compound was prepared by following the procedure ofexample 50, but replacing the product of example 44 with the product ofexample 151.

[0534]¹H-NMR (CDCl₃) δ: 1.55-1.88 (4H, m), 1.90-2.32 (2H, m), 2.10 (3H,s), 2.28-2.60 (5H, m), 2.82-3.02 (2H, m), 4.14 (2H, dd), 4.41 (2H, dd),5.29 (2H, brs), 6.08 (1H, t), 6.72-6.90 (3H, m), 7.18-7.34 (5H, m), 7.57(1H, m), 8.50 (1H, m).

[0535] MS m/z: 533 (M+1)

EXAMPLE 1574-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-hydroxyethyl)oxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine

[0536] The titled compound was prepared by following the procedure ofexample 51, but replacing the product of example 50 with the product ofexample 156.

[0537]¹H-NMR (CD₃OD) δ: 1.66-1.98 (4H, m), 2.40-2.73 (5H, m), 2.82-2.94(2H, m), 3.22 (2H, m), 3.84 (2H, dd), 4.01 (2H, dd), 5.23 (2H, brs),6.13 (1H, t), 6.64-6.98 (3H, m), 7.13-7.34 (4H, m), 7.45 (1H, m), 7.77(1H, m), 8.47 (1H, m). OH signal was not observed.

[0538] MS m/z: 491 (M+1)

EXAMPLE 1584-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-ethoxycarbonyl-1-methylethyl)oxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine

[0539] The titled compound was prepared by following the procedure ofexample 138, but replacing the product of example 44 with the product ofexample 151.

[0540]¹H-NMR (CDCl₃) δ: 1.28 (3H, t), 1.56 (6H, s), 1.56-1.85 (4H, m),1.97 (2H, dt), 2.28-2.55 (5H, m), 2.93 (2H, m), 4.24 (2H, q), 5.28 (2H,brs), 6.04 (1H, t), 6.62-6.95 (3H, m), 7.07-7.32 (5H, m), 7.57 (1H, dd),8.50 (1H, dd).

[0541] MS m/z: 561 (M+1)

EXAMPLE 1591-[3-(7-(1-Carboxy-1-methylethyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidine

[0542] The titled compound was prepared by following the procedure ofexample 133, but replacing the product of example 48 with the product ofexample 158.

[0543]¹H-NMR (CD₃OD) δ: 1.50 (6H, s), 1.82-2.18 (4H, m), 2.70 (2H, m),2.87 (1H, m), 3.12 (2H, m), 3.30 (2H, m), 3.60 (2H, m), 5.25 (2H, brs),6.07 (1H, t), 6.67-7.04 (3H, m), 7.16-7.38 (4H, m), 7.58 (1H, m), 7.96(1H, m), 8.52 (1H, m). COOH signal was not observed.

[0544] MS m/z: 533 (M+1)

EXAMPLE 1601-[3-(8-Bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidine

[0545] The titled compound was prepared by following the procedure ofexample 65, but replacing the product of example 45, step 2 with theproduct of example 54, step 1.

[0546]¹H-NMR (CDCl₃) δ: 1.50-1.86 (4H, m), 1.98 (2H, m), 2.26-2.60 (5H,m), 2.88 (2H, m), 5.30 (2H, brs), 6.09 (1H, t), 6.96-7.36 (8H, m), 7.57(1H, dd), 8.51 (1H, dd).

[0547] MS m/z: 509, 511 (M+1)

EXAMPLE 1611-[3-(8-Carboxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidine

[0548] To a solution of1-[3-(8-Bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidine(Example 160) (130 mg) in THF(1.0 ml) was added 1.6M n-butyllithiumhexane solution (0.17 ml) at −78° C. After stirring 10 minutes at thesame temperature, CO₂ (dry-ice) was added to the mixture. After beingwarmed to ambient temperature, the mixture was stirred for 30 minutes atthe same temperature. The mixture was concentrated in vacuo. Theresulting oil was purified by silica gel chromatography eluted withdichloromethane -methanol (5:1) to give the titled compound.

[0549]¹H-NMR (CD₃OD) δ: 1.55-1.95 (4H, m), 2.17 (2H, dt), 2.32-2.78 (5H,m), 3.00 (2H, m), 5.30 (2H, brs), 6.19 (1H, t), 7.08-7.54 (8H, m), 7.76(1H, dd), 8.45 (1H, dd). COOH signal was not observed (50 mg).

[0550] MS m/z: 475 (M+1)

EXAMPLE 1621-[3-(7-Bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0551] The titled compound was prepared by following the procedure ofexample 45, but replacing5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with8-bromo-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-one.

[0552]¹H-NMR (CDCl₃) δ: 1.60-1.71 (3H, m), 1.98-2.09 (2H, m), 2.34-2.69(8H, m), 5.32 (2H, brs), 6.13 (1H, t), 6.73 (1H, d), 7.22-7.44 (7H, m),7.57 (1H, dd), 8.52 (1H, dd).

[0553] MS m/z: 525, 527 (M+1)

EXAMPLE 1634-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-ethyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0554] The titled compound was prepared by following the procedure ofexample 45, but replacing5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with5,11-dihydro-7-ethyl[1]benzoxepino[2,3-b]pyridin-5-one.

[0555]¹H-NMR (CDCl₃) δ: 1.23 (3H, t), 1.52 (1H, brs), 1.66-1.71 (2H, m),1.98-2.06 (2H, m), 2.35-2.70 (1H, m), 5.31 (2H, brs), 6.09 (1H, t), 6.79(1H, d), 7.01 (1H, dd), 7.1 (1H, d), 7.25-7.44 (5H, m), 7.58 (1H, dd),8.49 (1H, dd).

[0556] MS m/z: 475 (M+1)

EXAMPLE 1644-(4-Chlorophenyl)-1-[3-(5,11-dihydro-8-vinyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0557] The titled compound was prepared by following the procedure ofexample 45, but replacing5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with5,11-dihydro-8-vinyl[1]benzoxepino[2,3-b]pyridin-5-one.

[0558]¹H-NMR (CDCl₃) δ: 1.66-1.71 (3H, m), 2.00-2.10 (2H, m), 2.36-2.70(8H, m), 5.22 (2H, d), 5.34 (2H, brs), 5.70 (1H, d), 6.1 1 (1H, t), 6.61(1H, dd), 6.89 (1H, d), 6.99 (1H, dd), 7.24-7.44 (6H, m), 7.58 (1H, dd),8.49 (1H, dd).

[0559] MS m/z: 473 (M+1)

EXAMPLE 1654-(4-Chlorophenyl)-1-[3-(5,11-dihydro-8-ethyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0560] A mixture of the product of example 164 (100 mg) and Pd-C (20 mg)in ethanol(2 ml) stirred under a hydrogen balloon at room temperaturefor 1 hour. The mixture was filtered through the celite and distilledoff under reduced pressure. The residue was purified by preparative thinlayer chromatography eluting with chloroform-methanol (15:1) to give thetitled compound (50 mg).

[0561]¹H-NMR (CDCl₃) δ: 1.22 (3H, t), 1.55-1.77 (3H, m), 2.00-2.13 (2H,m), 2.33-2.74 (10H, m), 5.32 (2H, brs), 6.07 (1H, t), 6.70 (1H, d), 6.78(1H, dd), 7.19-7.44 (6H, m), 7.57 (1H, dd), 8.49 (1H, dd).

[0562] MS m/z: 475 (M+1)

EXAMPLE 1664-(4-Chlorophenyl)-1-[3-(5,11-dihydro-9-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0563] The titled compound was prepared by following the procedure ofexample 45, but replacing5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with5,11-dihydro-9-methoxy[1]benzoxepino[2,3-b]pyridin-5-one.

[0564]¹H-NMR (CDCl₃) δ: 1.65-1.70 (2H, m), 1.95-2.06 (2H, m), 2.15 (1H,brs), 2.37-2.67 (8H, m), 3.83 (3H, s), 5.43 (2H, brs), 6.09 (1H, t),6.79-6.91 (3H, m), 7.22-7.43 (5H, m), 7.57 (1H, dd), 8.44 (1H, dd).

[0565] MS m/z: 477 (M+1)

EXAMPLE 1674-(4-Chlorophenyl)-1-[3-(5,11-dihydro[1]benzoxepino[4,3-c]pyridin-5-ylidene)propyl]piperidin-4-ol

[0566] The titled compound was prepared by following the procedure ofexample 45, but replacing5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with5,11-dihydro[1]benzoxepino[4,3-c]pyridin-5-one.

[0567]¹H-NMR (CDCl₃) δ: 1.67-1.71 (2H, m), 1.97-2.08 (2H, m), 2.16 (1H,s), 2.40-2.69 (8H, m), 5.16 (2H, brs), 6.14 (1H, t), 6.80 (1H, dd),6.91-6.97 (1H, m), 7.13-7.19 (1H, m), 7.26-7.44 (6H, m), 7.50-8.54 (2H,m).

[0568] MS m/z: 447 (M+1)

EXAMPLE 1684-(4-Chlorophenyl)-1-[3-(5,11-dihydro[1]benzoxepino[4,3-d]pyrimidin-5-ylidene)propyl]piperidin-4-ol

[0569] The titled compound was prepared by following the procedure ofexample 45, but replacing5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with5,11-dihydro[1]benzoxepino[4,3-d]pyrimidin-5-one.

[0570]¹H-NMR (CDCl₃) δ: 1.68-1.72 (2H, m), 1.90 (1H, brs), 2.06-2.19(2H, m), 2.41-2.78 (8H, m), 5.20 (2H, s), 6.12 (1H, t), 7.14-7.45 (8H,m), 8.72 (1H, s), 8.97 (1H, s).

[0571] MS m/z: 448 (M+1)

EXAMPLE 1694-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-trifluoromethanesulfonyloxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0572] To a solution of product of example 44 (1.0 g) in pyridine (10ml) was added trifluoromethanesulfonic acid anhydride (0.55 ml) at 0°C., and the mixture was stirred at room temperature for 1 hour. Waterand diethyl ether were added to the reaction mixture, the organic layerwas separated and washed with saturated aqueous sodium chloride, anddried with magnesium sulfate. The solvent was distilled off underreduced pressure, and the residue was purified by silica gelchromatography eluting with ethyl acetate-methanol (10:1) to give thetitled compound (1.1 g).

[0573]¹H-NMR (CDCl₃) δ: 1.56 (1H, brs), 1.66-1.71 (2H, m), 1.97-2.09(2H, m), 2.35-2.69 (8H, m), 5.35 (2H, brs) 6.15 (1H, t), 6.88 (1H, d),7.05 (1H, dd), 7.21-7.44 (6H, m), 7.60 (1H, dd), 8.54 (1H, dd).

[0574] MS m/z: 595 (M+1)

EXAMPLE 1701-[3-(7-Allyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0575] A mixture of the product of example 169 (240 mg),allyltributyltin (0.19 ml), dichlorobis(triphenylphosphine)palladium(II)(30 mg) and lithium chloride (76 mg) in dimethylformamide (3 ml) washeated under argon at 120° C. for 2 hours. Aqueous ammonium fluoridesolution and ethyl acetate were added to the reaction mixture, theorganic layer was separated and washed with saturated aqueous sodiumchloride, and dried with magnesium sulfate. The solvent was distilledoff under reduced pressure, and the residue was purified by silica gelchromatography eluting with chloroform-methanol (10:1) to give thetitled compound (180 mg).

[0576]¹H-NMR (CDCl₃) δ: 1.62-1.72 (3H, m), 2.03-2.11 (2H, m), 2.39-2.73(8H, m), 3.31 (2H, d), 5.04-5.11 (2H, m), 5.29 (2H, brs), 5.87-6.02 (1H,m), 6.06 (1H, t), 6.77 (1H, d), 6.99 (1H, dd), 7.10 (1H, d), 7.23-7.43(5H, m), 7.57 (1H, dd), 8.40 (1H, dd).

EXAMPLE 171

[0577]1-[3-(7-(2-t-Butoxycarboxy)ethenyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0578] A mixture of the product of example 169 (1.7 g), t-butyl acrylate(0.85 ml), triethylamine (2.5 ml), 1,1′-bis(diphenylphosphino)ferrocene(250 mg) and palladium(II) diacetate (33 mg) in dimethylformamide (3 ml)under argon at 90° C. for 24 hours. Water ethyl acetate were added tothe reaction mixture, the organic layer was separated and washed withsaturated aqueous sodium chloride, and dried with magnesium sulfate. Thesolvent was distilled off under reduced pressure, and the residue waspurified by silica gel chromatography eluting with ethylacetate-methanol (30:1) to give the titled compound (780 mg).

[0579]¹H-NMR (CDCl₃) δ: 1.45 (9H, s), 1.63-1.71 (3H, m), 1.98-2.10 (2H,m), 2.35-2.72 (8H, m), 5.35 (2H, brs), 6.15 (1H, t), 6.26 (1H, d), 6.83(1H, d), 7.22-7.44 (7H, m), 7.53 (1H, d), 7.58 (1H, dd), 8.52 (1H, dd).

EXAMPLE 1721-[3-(7-(2-Carboxy)ethenyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0580] The product of example 171 (330 mg) was dissolved with 4Nhydrochloric acid 1,4-dioxane solution (4 ml), and stirred at roomtemperature for 1 hour. The solvent was distilled off under reducedpressure. Water was added to the residue, and neutralized with sodiumhydroxide solution. The precipitation was filtered to give the titledcompound (190 mg).

[0581]¹H-NMR (DMSO-d₆) δ: 1.45-1.52 (2H, m), 1.72-1.84 (2H, m),2.25-2.58 (8H, m), 5.25 (2H, brs), 6.28 (1H, t), 6.43 (1H, d), 6.82 (1H,d), 7.34-7.60 (8H, m), 7.75 (1H, dd), 8.52 (1H, dd).

EXAMPLE 173

[0582]4-(4-Chlorophenyl)-1-[3-(5,11-dihydrd-7-propargyloxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0583] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with propargyl chloride.

[0584]¹H-NMR (CDCl₃) δ: 1.66-1.71 (2H, m), 1.79 (1H, brs), 1.99-2.10(2H, m), 2.35-2.71 (9H, m), 4.66 (2H, d), 5.28 (2H, brs), 6.10 (1H, t),6.80-6.93 (3H, m), 7.24-7.46 (5H, m), 7.59 (1H, dd), 8.48 (1H, dd).

[0585] MS m/z: 501 (M+1)

EXAMPLE 1744-(4-Chlorophenyl)-1-[3-(7-cyclopentoxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0586] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with cyclopentyl bromide.

[0587]¹H-NMR (CDCl₃) δ: 1.54-2.18 (13H, m), 2.41-2.72 (8H, m), 4.66-4.73(1H, m), 5.27 (2H, brs), 6.08 (1H, t), 6.70-6.87 (3H, m), 7.23-7.44 (5H,m), 7.58 (1H, dd), 8.49 (1H, dd).

[0588] MS m/z: 531 (M+1)

EXAMPLE 1754-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-methoxyethyl)oxy)[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0589] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with 2-methoxyethyl chloride.

[0590]¹H-NMR (CDCl₃) δ: 1.66-1.75 (3H, m), 2.00-2.11 (2H, m), 2.36-2.71(8H, m), 3.45 (3H, s), 3.71-3.75 (2H, m), 4.07-4.11 (2H, m), 5.27 (2H,brs), 6.09 (1H, t), 6.75-6.91 (3H, m), 7.23-7.44 (5H, m), 7.57 (1H, dd),8.48 (1H, dd).

[0591] MS m/z: 521 (M+1)

EXAMPLE 1764-(4-Chlorophenyl)-1-[3-(7-(1-dimethyaminocarbonyl-1-methyl)ethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0592] The titled compound was prepared by following the procedure ofexample 134, but replacing the product of example 133 with the productof example 139.

[0593]¹H-NMR (CDCl₃) δ: 1.59 (6H, s), 1.67-1.72 (2H, m), 1.99-2.09 (2H,m), 2.36-2.70 (9H, m), 2.96 (3H, s), 3.21 (3H, s), 5.25 (2H, brs), 6.02(1H, t), 6.60-6.77 (3H, m), 7.24-7.44 (5H, m), 7.58 (1H, dd), 8.44 (1H,dd).

[0594] MS m/z: 576 (M+1)

EXAMPLE 1774-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-ethoxycarbonylethyl)oxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0595] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with ethyl 2-bromopropionate.

[0596]¹H-NMR (CDCl₃) δ: 1.25 (3H, t), 1.59 (3H, d), 1.65-1.70 (2H, m),1.98-2.08 (2H, m), 2.35-2.68 (8H, m), 2.80 (1H, brs), 4.21 (2H, q), 4.68(1H, q), 5.24 (2H, brs), 6.07 (1H, t), 6.68-6.79 (2H, m), 6.88 (1H, d),7.22-7.44 (5H, m), 7.56 (1H, dd), 8.40 (1H, dd).

EXAMPLE 1781-[3-(7-(1-Carboxyethyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0597] The titled compound was prepared by following the procedure ofexample 133, but replacing product of example 48 with product of example177.

[0598]¹H-NMR (DMSO-d₆) δ: 1.46 (3H, d), 1.58-1.63 (2H, m), 1.98-2.06(2H, m), 2.41-2.45 (2H, m), 2.72-2.86 (6H, m), 4.74 (1H, q), 5.18 (2H,brs), 6.11 (1H, t), 6.73 (2H, s), 6.84 (1H, s), 7.36-7.47 (5H, m), 7.73(1H, dd), 8.50 (1H, dd).

[0599] MS m/z: 535 (M+1)

EXAMPLE 1794-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-ethoxycarbonyl)cyclobutoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0600] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with ethyl²-bromocyclobutanecarboxylate.

[0601]¹H-NMR (CDCl₃) δ: 1.19 (3H, t), 1.67-1.71 (2H, m), 1.92-2.11 (5H,m), 2.33-2.77 (12H, m), 4.21 (2H, q), 5.25 (2H, brs), 6.05 (1H, t), 6.47(1H, dd), 6.70 (1H, d), 6.73 (1H, d), 7.23-7.44 (5H, m), 7.55 (1H, dd),8.44 (1H, dd).

EXAMPLE 180

[0602]1-[3-(7-(1-Carboxy)cyclbutoxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0603] The titled compound was prepared by following the procedure ofexample 133, but replacing product of example 48 with product of example179.

[0604]¹H-NMR (DMSO-d₆) δ: 1.60-1.65 (2H, m), 1.86-20.08 (4H, m),2.24-2.90 (12H, m), 5.17 (2H, brs), 6.05 (1H, t), 6.50 (1H, dd), 6.66(1H, d), 6.73 (1H, d), 7.37-7.48 (5H, m), 7.74 (1H, dd), 8.51 (1H, dd).

[0605] MS m/z: 561 (M+1)

EXAMPLE 181

[0606]1-[3-(7-Carbamoylmethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0607] The titled compound was prepared by following the procedure ofexample 134, but replacing dimethylamine hydrochloride with ammoniumhydroxide.

[0608]¹H-NMR (CDCl₃) δ: 1.66-1.71 (2H, m), 1.98-2.09 (2H, m), 2.21 (1H,brs), 2.38-2.70 (8H, m), 4.45 (2H, s), 5.28 (2H, brs), 6.09 (1H, t), 6.11 (1H, brs), 6.58 (1H, brs), 6.74-6.85 (3H, m), 7.24-7.44 (5H, m), 7.58(1H, dd), 8.47 (1H, dd).

[0609] MS m/z: 520 (M+1)

EXAMPLE 1824-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methylaminocarbonylmethyloxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0610] The titled compound was prepared by following the procedure ofexample 134, but replacing dimethylamine hydrochloride with methylamine.

[0611]¹H-NMR (CDCl₃) δ: 1.67-1.72 (2H, m), 1.99-2.10 (2H, m), 2.36-2.70(9H, m), 2.89 (3H, d), 4.45 (2H, s), 5.28 (2H, brs), 6.08 (1H, t), 6.66(1H, brs), 6.73-6.84 (3H, m), 7.25-7.45 (5H, m), 7.58 (1H, dd), 8.47(1H, dd).

[0612] MS m/z: 534 (M+1)

EXAMPLE 1831-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl-4-(4-hydroxyphenyl)piperidine

[0613] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(4-hydroxyphenyl)piperidine.

[0614]¹H-NMR (CDCL3) δ: 1.52-1.88 (4H, m), 2.01 (2H, dt), 2.28-2.60 (5H,m), 2.93 (2H, m), 3.79 (3H, s), 5.28 (2H, brs), 6.08 (1H, t), 6.68-6.88(3H, m), 7.05-7.36 (5H, m), 7.58 (1H, dd), 8.50 (1H, dd).

[0615] MS m/z: 461 (M+1)

EXAMPLE 1841-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(2-hydroxyphenyl)piperidine

[0616] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(2-hydroxyphenyl)piperidine.

[0617]¹H-NMR (CDCl₃) δ: 1.78-1.92 (4H, m), 2.12-2.25 (2H, m), 2.32-2.70(4H, m), 2.80-2.97 (1H, m), 3.01-3.15 (2H, m), 3.77 (3H, s), 3.78 (1H,brs), 5.28 (2H, brs), 6.03 (1H, t), 6.74-6.86 (4H, m), 7.05 (1H, dd),7.11 (1H, dd), 7.23-7.28 (2H, m), 7.56 (1H, dd), 8.48 (1H, dd), OHsignal was not observed.

[0618] MS m/z: 443 (M+1)

EXAMPLE 1854-(7-Chloro-1,2-benzisoxazol-3-yl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine

[0619] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(7-chloro-1,2-benzisoxazol-3-yl) piperidine. This piperidine wasprepared by the same method described in J. Med. Chem. 28:761-769(1985).

[0620]¹H-NMR (CDCl₃) δ: 1.94-2.20 (6H, m), 2.30-2.60 (4H, m), 2.86-3.14(3H, m), 3.79 (3H, s), 5.29 (2H, brs), 6.10 (1H, t), 6.70-6.88 (3H, m),7.22 (1H, t), 7.27 (1H, dd), 7.50 (1H, dd), 7.57-7.68 (2H, m), 8.49 (1H,dd).

EXAMPLE 1864-(7-Chloroindol-3-yl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine

[0621] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(7-chloroindol-3-yl)piperidine. This piperidine was prepared bythe same method described in J. Med. Chem. 36:4006-4014 (1993) andfollowing hydrogenation described in Example 58, step 3.

[0622]¹H-NMR(CDCl₃) δ: 1.66-1.88 (2H, m), 1.92-2.22 (4H, m), 2.32-2.63(4H, m), 2.78 (1H, m), 2.97 (2H, m), 3.79 (3H, s), 5.29 (2H, brs), 6.09(1H, t), 6.70-6.87 (3H, m), 6.97-7.07 (2H, m), 7.12-7.30 (2H, m), 7.52(1H, m), 7.59 (1H, dd), 8.45 (1H, brs), 8.50 (1H, dd).

EXAMPLE 187

[0623]4-Azido-4-(4-chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidine

[0624] Step 1 4-azido-4-(4-chlorophenyl)piperidine (15): FIG. 8b

[0625] To a cold (0° C.) solution of 1 (3.0 g, 14 mmol) in anhydrousdioxane (15 mL) under an inert atmosphere was added NaN₃ (1.0 g, 15.4mmol) followed by the slow dropwise addition of and BF₃.OEt (4.4 mL, 35mmol). The reaction was stirred at 0° C. for 3 hrs and was quenched at0° C. by the slow careful addition of saturated aqueous NaHCO₃ tobasicity. The organic layer was separated and dried over Na₂SO₄. Thereaction mixture was purified via silica gel flash chromatographyeluting a 2 g 1:3 mixture of azidopiperidine 2 and olefin 3 with 2%MeOH/CH₂Cl₂. The mixture was taken directly on to the next reaction.

[0626] Step 2

[0627] The titled compound was prepared by then following the procedureof example 45, step 3, with the above reaction mixture (therebyreplacing 4-(4-chlorophenyl)-4-hydroxypiperidine with4-azido-4-(4-chlorophenyl)piperidine)), but limiting the amount ofbromide to 0.25 equivalents.

[0628]¹H-NMR (CDCL₃) δ: 1.88 (2H, m), 2.55-2.85 (4H, m), 3.00-3.30 (6H,m). 3.75 (3H, s), 5.19 (2H, brs), 5.97 (1H, t), 6.68-6.65 (3H, m),7.20-7.46 (5H, m), 7.63 (1H, dd), 8.35 (1H, dd).

[0629] MS m/z: 477 (M+1-N₂+H₂)

EXAMPLE 188

[0630] Methyl1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-phenylpiperidin-4-carboxylate

[0631] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith methyl 4-phenylpiperidin-4-carboxylate.

[0632]¹H-NMR (CDCl₃) δ: 1.82-2.15 (4H, m), 2.28-2.60 (6H, m), 2.78-2.82(2H, m), 3.62 (3H, s), 3.68 (3H, s), 5.26 (2H, brs), 5.95 (0.1H, t, Eisomer), 6.05 (0.9H, t, Z isomer), 6.82-6.70 (3H, m), 7.33-7.22 (6H, m),7.65 (0.1H, dd, Z isomer), 7.55 (0.9H, dd, Z isomer), 8.39 (0.1H, Eisomer), 8.48 (0.9H, dd, Z isomer).

[0633] MS m/z: 485 (M+1)

EXAMPLE 1891-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-phenylpiperidin-4-carboxylicAcid

[0634] The titled compound was prepared by following the procedure ofexample 133, but replacing product of example 48 with product-,ofexample 188.

[0635]¹H-NMR (CD₃OD) δ: 2.16-2.23 (2H, m), 2.69-2.91 (4H, m), 3.00-3.16(2H, m), 3.37-3.25 (2H, m), 3.68-3.73 (2H, m), 3.76 (3H, s), 5.34 (2H,brs), 6.24 (1H, t), 6.70-7.04 (3H, m), 7.26-7.55 (5H, m), 7.79-7.89 (1H,m), 8.21-8.34 (1H, m), 8.56-8.62 (0.1H, m), 8.63-8.77 (0.9H, m),

[0636] MS m/z: 471 (M+1)

EXAMPLE 1901-(2-Chlorophenylsulfonyl)-4-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperazine

[0637] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 1-(2-chlorophenylsulfonyl)piperazine.

[0638]¹H-NMR (CDCl₃) δ: 2.20-2.58 (8H, m), 3.12-3.38 (4H, m), 3.76 (3H,s), 5.22 (2H, brs), 6.03 (1H, t), 6.64-6.90 (3H, m), 7.23 (1H, dd),7.32-7.60 (4H, m), 8.01 (1H, dd), 8.48 (1H, dd).

[0639] MS m/z: 526 (M+1)

EXAMPLE 1911-(3-Chlorophenylsulfonyl)-4-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperazine

[0640] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 1-(3-chlorophenylsulfonyl)piperazine.

[0641]¹H-NMR (CDCl₃) δ: 2.20-2.60 (8H, m), 2.82-3.12 (4H, m), 3.76 (3H,s), 5.18 (2H, brs), 6.00 (1H, t), 6.64-6.90 (3H, m), 7.23 (1H, dd),7.42-7.78 (5H, m), 8.48 (1H, dd).

[0642] MS m/z: 526 (M+1)

EXAMPLE 1921-(4-Chlorophenylsulfonyl)-4-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperazine

[0643] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 1-(4-chlorophenylsulfonyl)piperazine.

[0644]¹H-NMR (CDCl₃) δ: 2.20-2.56 (8H, m), 2.82-3.10 (4H, m), 3.76 (3H,s), 5.18 (2H, brs), 5.99 (1H, t), 6.62-6.92 (3H, m), 7.23 (1H, dd),7.42-7.78 (5H, m), 8.48 (1H, dd).

[0645] MS m/z: 526 (M+1)

EXAMPLE 1934-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-1,2,3,6-tetrahydropyridine

[0646] The titled compound was prepared by following the procedure ofexample 44, step 2, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine.

[0647]¹H-NMR (CDCl₃) δ: 2.37-2.72 (8H, m), 3.07 (2H, m), 5.25 (2H, brs),6.00 (1H, m), 6.07 (1H, t), 6.60-6.78 (3H, m), 7.18-7.47 (5H, m), 7.56(1H, dd), 8.50 (1H, dd). OH signal was not observed.

[0648] MS m/z: 445 (M+1)

EXAMPLE 1944-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-1,2,3,6-tetrahydropyridine

[0649] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(4-chlorophenyl)-1,2,3,6-tetrahydropyridine.

[0650]¹H-NMR (CDCl₃) δ: 2.37-2.72 (8H, m), 3.06 (2H, m), 3.78 (3H, s),5.27 (2H, brs), 5.99 (1H, m), 6.10 (1H, t), 6.72-6.90 (3H, m), 7.20-7.44(5H, m), 7.60 (1H, dd), 8.50 (1H, dd).

[0651] MS m/z: 459 (M+1)

EXAMPLE 1954-(7-Chloroindol-3-yl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-1,2,3,6-tetrahydropyridine.

[0652] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(7-chloroindol-3-yl)-1,2,3,6-tetrahydropyridine. This piperidinewas prepared by the same method described in J. Med. Chem. 36:4006-4014(1993).

[0653]¹H-NMR (CDCl₃) δ: 2.37-2.76 (8H, m), 3.14 (2H, m), 3.78 (3H, s),5.29 (2H, brs), 6.02-6.23 (2H, m), 6.67-6.90 (3H, m), 7.05 (1H, dd),7.12-7.33 (3H, m), 7.60 (1H, dd), 7.77 (1H, m), 8.50 (1H, dd), 9.06 (1H,br s).

EXAMPLE 196

[0654]5-Chloro-1′-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]spiro[isobenzofuran-1(3H), 4′-piperidine]

[0655] The titled compound was prepared by following the procedure ofexample 44, step 2, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 5-chlorospiro[isobenzofuran-1 (3H), 4′-piperidine].

[0656]¹H-NMR (CDCl₃) δ: 1.66-1.71 (2H, m), 1.79-1.91 (2H, m), 2.26-2.73(8H, m), 4.99 (2H, s), 5.22 (2H, brs), 6.07 (1H, t), 6.63-6.70 (2H, m),6.76 (1H, d), 7.06 (1H, d), 7.19-7.32 (3H, m), 7.60 (1H, dd), 8.47 (1H,dd), 8.63 (1H, s).

[0657] MS m/z: 475 (M+1)

EXAMPLE 1975-Chloro-1′-[3-(5,11-dihydro-7-(2-methoxyethyl)oxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]spiro[isobenzofuran-1(3H), 4′-piperidine]

[0658] The titled compound was prepared by following the procedure ofexample 175, but replacing the product of example 44 with the product ofexample 196.

[0659]¹H-NMR (CDCl₃) δ: 1.69-1.74 (2H, m), 1.83-1.94 (2H, m), 2.31-2.76(8H, m), 3.45 (3H, s), 3.72-3.75 (2H, m), 4.08-4.11 (2H, m), 5.00 (2H,s), 5.28 (2H, brs), 6.09 (1H, t), 6.74-6.82 (2H, m), 6.89 (1H, d), 7.04(1H, d), 7.17-7.28 (3H, m), 7.57 (1H, dd), 8.49 (1H, dd).

[0660] MS m/z: (M+1)

EXAMPLE 1984-(4-Chlorophenyl)-1-[3-(7-dimethylaminocarbonyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0661] The titled compound was prepared by following the procedure ofexample 134, but replacing the product of example 133 with the productof example 118.

[0662]¹H-NMR (CDCl₃) δ: 1.65-1.70 (2H, m), 1.99-2.09 (3H, m), 2.32-2.69(8H, m), 2.17 (3H, s), 5.35 (2H, brs), 6.15 (1H, t), 6.82 (1H, d), 7.19(1H, dd), 7.28-7.46 (6H, m), 7.58 (1H, dd), 8.49 (1H, dd).

EXAMPLE 1994-(4-Chlorophenyl)-1-[3-(7-(2-(1-hydroxy-2-methyl)propyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0663] To a solution of product of example 138 (500 mg) in methanol (5ml) was added sodium borohydride (330 mg), and the mixture was heated toreflux for 1 hour. The mixture was distilled off under reduced pressure.Water and ethyl acetate were added to the residue, the organic layer wasseparated and washed with saturated aqueous sodium chloride, and driedwith magnesium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by silica gel chromatographyeluting with chloroform-methanol (10:1) to give the titled compound (440mg).

[0664]¹H-NMR (CDCl₃) δ: 1.26 (6H, s), 1.66-1.70 (2H, m), 1.79 (1H, brs),2.00-2.08 (2H, m), 2.37-2.70 (9H, m), 3.58 (2H, s), 5.30 (2H, brs), 6.05(1H, t), 6.75-6.84 (2H, m), 6.91 (1H, d), 7.26-7.44 (5H, m), 7.58 (1H,dd), 8.49 (1H, dd).

[0665] MS m/z: 535 (M+1)

EXAMPLE 2004-(4-Chlorophenyl)-1-[3-(7-(1-(2-methyl-2-hydroxy)propyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0666] To a solution of product of example 48 (500 mg) intetrahydrofuran (5 ml) was added 0.95M methylmagnesium bromidetetrahydrofuran solution (3.8 ml) at 0° C., and the mixture was stirredat room temperature for 20 minutes. Aqueous ammonium chloride solutionand ethyl acetate were added to the mixture, the organic layer wasseparated and washed with saturated aqueous sodium chloride, and driedwith magnesium sulfate. The solvent was distilled off under reducedpressure, and the residue was purified by silica gel chromatographyeluting with chloroform-methanol (10:1) to give the titled compound (360mg).

[0667]¹H-NMR (CDCl₃) δ: 1.34 (6H, s), 1.58 (1H, brs), 1.66-1.71 (2H, m),1.99-2.10 (2H, m), 2.25 (1H, brs), 2.36-2.71 (8H, m), 3.77 (2H, s), 5.28(2H, brs), 6.09 (1H, t), 6.74-6.86 (3H, m), 7.24-7.44 (5H, m), 7.57 (1H,dd), 8.49 (1H, dd).

[0668] MS m/z: 535 (M+1)

EXAMPLE 203

[0669]4-(4-Chlorophenyl)-1-[3-(7-(2-ethoxy)ethyloxy)-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0670] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with 2-ethoxyethyl bromide.

[0671]¹H-NMR (CDCl₃) δ: 1.24 (3H, t), 1.66-1.75 (3H, m), 2.00-2.11 (2H,m), 2.36-2.71 (8H, m), 3.59 (2H, q), 3.71-0.75 (2H, m), 4.07-4.11 (2H,m), 5.27 (2H, brs), 6.09 (1H, t), 6.75-6.91 (3H, m), 7.23-7.44 (5H, m),7.57 (1H, dd), 8.48 (1H, dd).

[0672] MS m/z: 535 (M+1)

EXAMPLE 205

[0673]4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-(2,3-dihydroxy)propyloxy)[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0674] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with glycidol.

[0675]¹H-NMR (CDCl₃) δ: 1.66-1.75 (2H, m), 2.00-2.11 (2H, m), 2.36-2.71(8H, m), 3.62-3.76 (2H, m), 3.94-4.02 (4H, m), 4.21 (2H, brs), 5.27 (2H,brs), 6.09 (1H, t), 6.76-6.86 (3H, m), 7.23-7.44 (5H, m), 7.57 (1H, dd),8.48 (1H, dd).

[0676] MS m/z: 537 (M+1)

EXAMPLE 211

[0677]1-[3-(7-(1-Carbamoyl-1-methyl)ethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0678] The titled compound was prepared by following the procedure ofexample 176, but replacing dimethylamine hydrochloride with ammoniumhydroxide.

[0679]¹H-NMR (CDCl₃) δ: 1.50 (6H, s), 1.67-1.72 (2H, m), 1.96-2.09 (3H,m), 2.36-2.70 (8H, m), 5.30 (2H, brs), 5.70 (1H, brs), 6.05 (1H, t),6.75-6.90 (4H, m), 7.25-7.44 (5H, m), 7.58 (1H, dd), 8.49 (1H, dd).

[0680] MS m/z: 548 (M+1)

EXAMPLE 212

[0681]4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-methylaminocarbonyl-1-methyl)ethyloxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0682] The titled compound was prepared by following the procedure ofexample 176, but replacing dimethylamine hydrochloride with methylamine.

[0683]¹H-NMR (CDCl₃) δ: 1.47 (6H, s), 1.67-1.72 (2H, m), 1.96-2.09 (2H,m), 2.20 (1H, brs), 2.36-2.70 (8H, m), 2.87 (3H, d), 5.29 (2H, brs),6.04 (1H, t), 6.72-6.86 (4H, m), 7.27-7.44 (5H, m), 7.58 (1H, dd), 8.47(1H, dd).

[0684] MS m/z: 562 (M+1)

EXAMPLE 215

[0685]4-(4-Chlorophenyl)-1-[3-(7-(2-dimethylaminocarboxy)ethenyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0686] The titled compound was prepared by following the procedure ofexample 134, but replacing the product of example 133 with the productof example 172.

[0687]¹H-NMR (CDCl₃) δ: 1.63-1.71 (3H, m), 1.98-2.10 (2H, m), 2.35-2.72(8H, m), 3.07 (3H, s), 3.17 (3H, s), 5.36 (2H, brs), 6.16 (1H, t), 6.76(1H, d), 6.84 (1H, d), 7.28-7.45 (7H, m), 7.59-7.65 (2H, m), 8.52 (1H,dd).

[0688] MS m/z: 544 (M+1)

EXAMPLE 218

[0689]1-[3-(7-(2-Carbamoyl)ethyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol

[0690] The titled compound was prepared by following the procedure ofexample 181, but replacing the product of example 133 with the productof example 123.

[0691]¹H-NMR (CDCl₃) δ: 1.65-1.90 (3H, m), 2.10-2.22 (2H, m), 2.40-2.80(10H, m), 2.91 (2H, t), 5.31-5.46 (4H, m), 6.1 1 (1H, t), 6.78 (1H, d),7.01 (1H, dd), 7.16 (1H, d), 7.28-7.46 (5H, m), 7.57 (1H, dd), 8.49 (1H,dd).

[0692] MS m/z: 518 (M+1)

EXAMPLE 2341-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidine)propyl]-4-(indol-3-yl)-piperidine

[0693] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(indol-3-yl)-piperidine. This piperidine was prepared by the samemethod described in J. Med. Chem. 36:4006-4014 (1993) and followhydrogenation described in Example 58, step 3.

[0694]¹H-NMR(CDCl₃) δ: 1.65-1.93 (2H, m), 1.94-2.28 (4H, m), 2.34-2.70(4H, m), 2.81 (1H, m), 2.96 (2H, m), 3.78 (3H, s), 5.28 (2H, brs), 6.09(1H, t), 6.70-7.42 (8H, m), 7.53-7.72 (2H, m), 8.28 (1H, brs), 8.49 (1H,m).

EXAMPLE 2351-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidine)propyl]-4-(indol-3-yl)-1,2,3,6-tetrahydropyridine

[0695] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 4-(indol-3-yl)-1,2,3,6-tetrahydropyridine. This piperidine wasprepared by the same method described in J. Med. Chem. 36:4006-4014(1993).

[0696]¹H-NMR (CDCl₃) δ: 2.35-2.77 (8H, m), 3.06-3.26 (2H, m), 3.78 (3H,s), 5.29 (2H, brs), 6.05-6.22 (2H, m), 6.70-6.88 (3H, m), 7.07-7.38 (5H,m), 7.60 (1H, dd), 7.87 (1H, m), 8.42 (1H, brs), 8.50 (1H, m).

EXAMPLE 2364-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(3-(ethoxycarbonyl)propyloxy[1]benzoxipino[2,3-b]pyridin-5-ylidine)propyl]piperidine

[0697] The titled compound was prepared by following the procedure ofexample 153, but replacing ethyl bromoacetate with ethyl4-bromobutyrate.

[0698]¹H-NMR (CDCL₃) δ: 1.26 (3H, t), 1.56-1.85 (4H, m), 2.01 (2H, dt),2.09 (2H, quint), 2.30-2.60 (7H, m), 2.93 (2H, m), 3.98 (2H, t), 4.15(2H, q), 5.28 (2H, brs), 6.07 (1H, t), 6.68-6.86 (3H, m), 7.07-7.33 (5H,m), 7.58 (1H, dd), 8.50 (1H, dd).

[0699] MS m/z: 561 (M+1)

EXAMPLE 2371-[3-(7-(3-Carboxypropyl)oxy-5,11-dihydro-[1]benzoxepino[2,3-b]pyridin-5-ylidine)propyl]-4-(4-chlorophenyl)-piperidine

[0700] The titled compound was prepared by following the procedure ofexample 133, but replacing the product of example 48 with the product ofexample 236.

[0701]¹H-NMR (CD₃OD) δ: 1.92-2.20 (6H, m), 2.48 (2H, t), 2.70-3.02 (3H,m), 3.06-3.45 (4H, m), 3.66 (2H, m), 4.01 (2H, t), 5.48 (2H, brs), 6.36(1H, t), 6.85 (2H, s), 7.00 (1H, s), 7.20-7.40 (4H, m), 8.1 1 (1H, dd),8.64 (1H, d), 8.81 (1H, d). COOH signal was not observed.

[0702] MS m/z: 533 (M+1)

EXAMPLE 242

[0703]4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-hydroxy-1-methyl)ethyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-olThe titled compound was prepared by following the procedure of example200, but replacing the product of example 48 with the product of exampleKF72112.

[0704]¹H-NMR (CDCl₃) δ: 1.58 (6H, s), 1.65-1.70 (3H, m), 1.93-2.21 (2H,m), 2.28-2.73 (8H, m), 5.32 (2H, brs), 6.13 (1H, t), 6.82 (1H, d),7.20-7.50 (7H, m), 7.59 (1H, dd), 8.50 (1H, dd)

[0705] MS m/z: 505 (M+1)

EXAMPLE 2481′-[3-(5,11-Dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidine)propyl]-6-methylspiro[4H-3,1-benzoxazine-4,4′-piperidine]-2(1H)-one

[0706] The titled compound was prepared by following the procedure ofexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 6-methylspiro[4H-3,1-benzoxazine-4,4′-piperidin]-2 (1H)-one.

[0707]¹H-NMR (CDCl₃) δ: 1.99-2.06 (2H, m), 2.29 (3H, s), 2.32-2.69 (10H,m), 3.77 (3H, s), 5.27 (2H, brs), 6.08 (1H, t), 6.69-6.83 (4H, m), 6.94(1H, s), 7.02 (1H, d), 7.25 (1H, dd), 7.55 (1H, dd), 8.48 (1H, dd), 8.56(1H, s).

[0708] MS m/z: 498 (M+1)

EXAMPLE 2495-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4,6-dioxazacane

[0709]5-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4,6-diazacyclooctylamine

[0710] Step 1

[0711]5-(3-(N,N′-Bis(2-hydroxyethyl)amino)propylidene)-5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridinewas prepared by following the procedure of example 45, step 3, butreplacing 4-(4-chlorophenyl)-4-hydroxypiperidine with diethanolamine.

[0712]¹H-NMR (CD₃OD) δ: 2.46 (2H, m), 2.84 (4H, t), 2.98 (2H, m), 3.67(4H, t), 3.75 (3H, s), 5.20 (2H, brs), 6.16 (1H, t), 6.68-6.80 (2H, m),6.87 (1H, d), 7.46 (1H, dd), 7.81 (1H, dd), 8.45 (1H, dd).

[0713] Step 2

[0714] To a mixture of product of step 1 (78 mg) and4-chlorobenzaldehyde dimethyl acetal (0.1 ml) in 1,2-dichloroethane (60ml) was added p-toluenesulfonic acid monohydrate (5 mg) at roomtemperature, and the mixture was stirred at reflux for 12 hours.Dichloromethane and saturated aqueous sodium bicarbonate was added tothe cooled reaction mixture, the organic layer was separated and washedwith saturated aqueous sodium chloride, and dried with magnesiumsulfate. The solvent was distilled off under reduced pressure, and theresidue was purified by silica gel chromatography eluting withdichloromethane-methanol (20:1) to give the titled compound (40 mg).

[0715]¹H-NMR (CDCl₃) δ: 2.35 (2H, m), 2.64-2.94 (6H, m), 3.52-3.68 (2H,m), 3.78 (3H, s), 3.72-3.90 (2H, m), 5.27 (2H, brs), 5.66 (1H, s), 6.08(1H, t), 6.68-6.88 (3H, m), 7.18-7.46 (5H, m), 7.58 (1H, dd), 8.50 (1H,dd).

EXAMPLE 252

[0716] Step 1

[0717] To a cold (0° C.) stirred solution of 4-oxohomopiperidine.HCl(0.6 g, 4.05 mmol), K₂CO₃ (0.615 g, 4.46 mmol) in anhydrous THF (10 mL)will be ethyl chloroformate (0.44 mL, 4.05 mmol) dropwise. The reactionwas warmed to RT for 2 hrs then quenched with H₂O, extracted with EtOAc,and the organic layer dried over Na₂SO₄. Pure1-ethylcarbonyl-4-oxohomopiperidine will be isolated via silica gelflash chromatography

[0718] Step 2

[0719] To a cold (0° C.) stirred solution of1-ethylcarbonyl-4-oxohomopiperidine (1.42 g, 6.07 mmol) in anhydrous THF(50 mL) under argon can be added dropwise 1.o mM 4-chlorophenylmagnesiumbromide in diethyl ether (10 mL, 10 mmol). The reaction can be warmed toRT for 2 hrs then quenched with saturated aqueous NH₄Cl 95 mL). Thereaction mixture can then be extracted with EtOAc (2×50 mL), the organiclayers combined and dried over Na₂SO₄. Pure1-ethoxycarbonyl-4-(4-chlorophenyl)-4-hydroxyhomopeperidine (2.1 g, 96%)can be isolated via silica gel flash chromatography eluting with 50%ETOAc/hexane.

[0720] 4-(4-chlorophenyl)-4-hydroxyhomopiperidine can be prepared byreacting 1-ethoxycarbonyl-4-(4-chlorophenyl)-4-hydroxyhomopeperidinewith a nucleophilic hydroxide equivalent such as LiOH in a solvent suchas THF, methanol or ethanol. Removal of the solvent can afford4-(4-chlorophenyl)-4-hydroxyhomopeperidine.

[0721] Step 4

[0722] The compound was prepared by following the procedure for Example44, but replacing 4-(4-chlorophenyl)-4-hydroxypeperidine with4-(4-chlorophenyl)-4-hydroxyhomopeperidine.

EXAMPLES 253 AND 254

[0723] Step 1

[0724] To a stirred solution of 4-oxohomopiperidine.HCl (1.2 g, 8.05mmol), NaOH (0.68 g, 16.9 mmol) in t-BuOH/H₂O (1:1, 10 mL) was addedt-butyldicarbonate (1.93 mL, 8.9 mmol) drop-wise. The reaction wasstirred at RT overnight, extracted with EtOAc (2×10 mL) and the organiclayer separated. The organic layer was dried over Na₂SO₄ andconcentrated under vacuo. Pure 1-t-butoxycarbonyl-4-oxohomopiperidine(1.42 g, 84%) was isolated via silica gel flash chromatography elutingwith 50% EtOAc/hexane.

[0725]¹H-NMR CDCl₃ δ: 44 (9H, s), 1.72-1.84 (2H, m), 2.60-2.65 (4H, m),3.55-3.61 (4H, m).

[0726] Step 2

[0727] To a cold (0° C.) stirred solution of1-t-butoxycarbonyl-4-oxohomopiperidine (1.42 g, 6.07 mmol) in anhydrousTHF (50 mL) under argon was added dropwise 1.0 M 4-chlorophenylmagnesiumbromide in diethyl ether (10 mL, 10 mmol). The reaction was warmed to RTfor 2 hrs then quenched with sat'd aqueous NH₄Cl (5 mL). The reactionmixture was extracted with EtOAc (2×50 mL), the organic layers combinedand dried over Na₂SO₄. Pure1-t-butoxycarbonyl-4-(4-chlorophenyl)-4-hydroxyhomopiperidine (2.1 g,96%) was isolated via silica gel flash chromatography eluting with 50%EtOAc/hexane. ¹H-NMR CDCl₃δ: 1.43 (9H, s), 1.61-2.22 (6H, m), 3.21-3031(2H, m), 3.48-3.82 (2H, m).

[0728] Step 3

[0729] To a stirred solution of1-t-butoxycarbonyl-4-(4-chlorophenyl)-4-hydroxyhomopiperidine (2.1 g) atRT in CH₂Cl₂ (48 mL) was added TFA (2.0 mL). The reaction was stirred atRT for 2 hrs. Excess solvent and TFA was removed affording 2.0 g (92%yield) 1:1 mixture of 3-(4-chlorophenyl)-2,3-dehydrohomopiperidine and3-(4-chlorophenyl)-3,4-dehydrohomopiperidine. ¹H NMR (MeOD, isomer A) δ2.01-2.11 (2H, m, 4), 2.60-2.71 (2H, m, 5), 2.81-2.92 (2H, m, 4),2.83-3.05 (2H, m, 5), 3.66-3.92 (4H, m, 5), 6.16-6.21 (1H, t, 5). ¹H NMR(MeOD, isomer B) 3.44-3.56 (2H, m, 4), 3.88-3.97 (2H, m, 4), 6.01-6.12(1H, t, 4), 7.32-7.44 (1H, t, 4).

[0730] Step 4

[0731] The compounds can be prepared by following the procedure forExample 44 but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with3-(4-chlorophenyl)-3,4-dehydrohomopiperidine and3-(4-chlorophenyl)-4,5-dehydrohomopiperidine.

EXAMPLE 255

[0732]1-(4-Chlorophenyl)-4-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperazinone

[0733] The titled compound was prepared by following the procedure ofexample 44, step 2, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 1-(4-chlorophenyl)piperazinone.

[0734]¹H-NMR (DMSO-d₆) δ: 2.30-2.34 (2H, m), 2,49-2.57 (2H, m), 2.68(2H, t), 3.06 (2H, s), 3.58 (2H, t), 5,12 (2H, brs), 6.06 (2H, t),6.57-6.69 (3H, m), 7.35-7.71 (5H, m), 7.72 (1H, dd), 8.48 (1H, dd).

EXAMPLE 256

[0735]1-(4-Chlorophenyl)-4-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]homopiperazdine

[0736] The titled compound was prepared by following the procedure ofexample 44, step 2, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 1-(4-chlorophenyl)homopiperazdine.

[0737]¹H-NMR (CDCl₃) δ: 1.89 (2H, brs), 2.27-2.35 (2H, m), 2.51-2.70(6H, m), 3.37-3.53 (4H, m), 5.23 (2H, brs), 5.98 (1H, t), 6.48-6.74 (6H,m), 7.05-7.26 (2H, m), 7.52 (1H, dd), 8.45 (1H, dd).

[0738] MS m/z: 462 (M+1)

EXAMPLE 260

[0739]3-(4-Chlorophenyl)-8-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-8-azabicyclo[3.2.1]octan-3-olThe titled compound was prepared by following the procedure of example44, step 2, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with3-(4-chlorophenyl)-8-azabicyclo[3.2.1]octan-3-ol

[0740]¹H-NMR(CDCl₃) δ:1.65-2.10 (4H, m), 2.1-2.7 (8H, m), 3.32 (2H, bs),3.78 (3H, s), 5.24 (2H, bs), 6.10 (1H, dd), 6.70-6.90 (3H, m), 7.15-7.31(3H, m), 7.45 (bd, 2H), 7.64 (dd, 1H), 8.46 (dd, 11H)

[0741] MS m/z: 503 (M+1)

EXAMPLE 261

[0742]1′-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-hydroxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]spiro[5-chloro-1,3-benzodioxole-2,4′-piperidine]

[0743] The titled compound was prepared by following the procedure ofexample 44, step 2, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith spiro[5-chloro-1,3-benzodioxole-2,4′-piperidine] (Journal ofMedicinal Chemistry. 1995, 38, 2009-2017).

[0744]¹H-NMR(DMSO-d₆) δ: 1.78-2.02 (4H, m), 2.18-2.63 (8H, m), 4.97-5.27(2H, brs), 6.06 (1H, t), 6.58-6.67 (3H, m), 6.79-6.87 (2H, m), 6.99 (1H,d), 7.42 (1H, dd), 7.72 (1H, dd), 8.49 (1H, dd), 9.07 (1H, s).

EXAMPLE 262

[0745]1-[3-(7-(1-Carbamoyl-1-methyl)ethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)-4-hydroxy-1-methylpiperidiniumIodide

[0746] To a solution of the product of example 211 (330 mg) and inacetonitrile (1.2 ml) was added iodomethane (0.07 ml), and the reactionmixture was stirred at room temperature for 2 hours. The precipitationwas filtered and washed with acetonitrile to give the titled compound(250 mg).

[0747]¹H-NMR (DMSO-d₆) δ: 1.39 (6H, s), 1.65-1.85 (2H, m), 2.20-2.64(4H, m), 3.09 (3H, s), 3.30-3.65 (6H, m), 5.20 (2H, m), 5.61 (1H, s),6.01 (1H, t), 6.75-6.92 (3H, m), 7.27 (1H, s), 7.38-7.64 (6H, m), 7.83(1H, dd), 8.56 (1H, dd)

[0748] MS m/z: 562[(M−I)+]

EXAMPLE 263

[0749]4-(4-Chlorophenyl)-1-[3-(7-diethylaminocarbonylmethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0750] The titled compound was prepared by following the procedure ofexample 134, but replacing dimethylamine hydrochloride withdiethylamine.

[0751]¹H-NMR (CDCl₃) δ: 1.67-1.72 (2H, m), 1.99-2.10 (2H, m), 2.36-2.70(9H, m), 2.89 (3H, d), 4.45 (2H, s), 5.28 (2H, brs), 6.08 (1H, t), 6.66(1H, brs), 6.73-6.84 (3H, m), 7.25-7.45 (5H, m), 7.58 (1H, dd), 8.47(1H, dd).

[0752] MS m/z: 534 (M+1)

EXAMPLE 269

[0753]1-[3-(7-Carbamoyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0754] The titled compound was prepared by following the procedure ofexample 198, but replacing dimethylamine hydrochloride with ammoniumhydroxide.

[0755]¹H-NMR (CDCl₃) δ: 1.67-1.79 (2H, m), 2.01-2.10 (2H, m), 2.17-2.71(8H, m), 5.38 (2H, brs), 6.21 (1H, t), 6.85 (1H, d), 7.27-7.57 (9H, m),7.90 (1H, dd), 8.50 (1H, dd).

[0756] MS m/z: 490 (M+1)

EXAMPLE 273

[0757]4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(methoxycarbonyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0758] A mixture of the product of example 169 (15.0 g), palladium(II)diacetate (170 mg), 1,3-bis(diphenylphosphino)propane (31 0 mg), andtriethylamine (7.0 ml) in methanol (100 ml) and dimethylformamide (150ml) was purged with carbon monoxide for 5 minutes and stirred under acarbon monoxide balloon at 70° C. for 8 hours. The reaction mixture wasevaporated under reduced pressure. The residue was added water andextracted with ethyl acetate. The extract was dried over magnesiumsulfate, and the solvent was evaporated under reduced pressure. Theresidue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1) to give the titled compound(13.1 g).

[0759]¹H-NMR(CDCl₃) δ: 1.45-1.80 (3H, m), 1.90-2.15 (2H, m), 2.28-2.48(4H, m), 2.50-2.75 (4H, m), 3.89(3H, s), 5.25-5.50(2H, m), 6.20(1H, dd),6.85(1H, d), 7.20-7.37(3H, m), 7.42(2H, d), 7.58(1H, d), 7.80(1H, dd),8.01(1H, dd), 8.52(1H, dd)

[0760] MS m/z: 505(M+1)

EXAMPLE 274

[0761]4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-hydroxymethyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0762] To an ice-cooled solution of the product of example 273 (2.0 g)in tetrahydrofuran (100 ml) was added lithium aluminum hydride (300 mg),and the reaction mixture was stirred at room temperature for 12 hours.After the reaction mixture was cooled to 0° C., water (0.3 ml), 15%sodium hydroxide aqueous solution (0.3 ml), and water (0.9 ml) wereadded. The reaction mixture was filtered, and the filtrate was driedover magnesium sulfate. The solvent was evaporated under reducedpressure and the residue was purified by silica gel columnchromatography (chloroform:methanol: 28% ammonia in water=100:5:1) togive the titled compound (1.6 g).

[0763]¹H-NMR (CDCl₃) δ: 1.55-1.71(3H, m), 1.95-2.25(2H, m),2.34-2.70(8H, m), 4.62(2H, s), 5.20-5.45(2H, brs), 6.13(1H, t), 6.84(1H,d), 7.16(1H, dd), 7.23-7.43(6H, m), 7.58(1H, dd), 8.51(1H, dd)

[0764] MS m/z: 477(M+1)

EXAMPLE 275

[0765]4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-propylamino)methyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0766] To a solution of the product of example 314 (300 mg) and1-propylamine (0.26 ml) in tetrahydrofuran (6 ml) was added acetic acid(0.36 ml), and the reaction mixture was stirred at 60° C. for 30minutes. Then the reaction mixture was added sodiumtriacetoxyborohydride (670 mg) at 0° C., and stirred for 1.5 hours atroom temperature. Sodium bicarbonate, water, and chloroform were addedto the reaction mixture. The organic layer was extracted, and dried overpotassium carbonate, and evaporated under reduced pressure. The residuewas recrystallized with ethyl acetate to give titled compound (130 mg).

[0767]¹H-NMR (CDCl₃) δ: 0.92 (3H, t), 1.49-1.70 (6H, m), 1.98 (2H, m),2.34-2.42 (4H, m), 2.51-2.70 (6H, m), 3.71 (2H, s), 5.32 (2H, brs), 6.12(1H, t), 6.8 1 (1H, d), 7.1 1 (1H, dd), 7.25-7.45 (6H, m), 7.57 (1H,dd), 8.49 (1H, dd).

[0768] MS m/z: 518 (M+1)

EXAMPLE 279

[0769] 4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-pyrrolidino)methyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0770] The titled compound was prepared by following the procedure ofExample 275, but replacing 1-propylamine with 4-aminobutyric acid.

[0771]¹H-NMR (CDCl₃) δ: 1.70-1.75 (2H, m), 1.98 (2H, m), 2.12-2.23 (2H,m), 2.40-2.86 (10H, m), 3.27 (2H, t), 4.36 (2H, s), 5.29 (2H, brs), 6.07(1H, t), 6.80 (1H, d), 7.04 (1H, dd), 7.19 (1H, d), 7.28-7.32 (3H, m),7.50 (1H, t), 7.61 (1H, dd), 8.51 (1H, dd).

[0772] MS m/z: 544 (M+1)

EXAMPLE 280

[0773]4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-hydroxy)ethyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0774] The titled compound was prepared by following the procedure ofexample 273, but replacing the product of example with the product ofexample 274.

[0775]¹H-NMR (CDCl₃) δ: 1.60-1.70 (4H, m), 2.01-2.12 (2H, m), 2.37-2.70(8H, m), 2.81 (2H, t), 3.84 (2H, t), 5.31 (2H, brs), 6.09 (1H, t), 6.81(1H, d), 7.03 (1H, dd), 7.15 (1H, d), 7.26-7.43 (5H, m), 7.57 (1H, dd),8.49 (1H, dd).

[0776] MS m/z: 491 (M+1)

EXAMPLE 281

[0777]1-[3-(7-Carbamoylmethyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-olThe titled compound was prepared by following the procedure of example122, but replacing dimethylamine hydrochloride with ammonium hydroxide.

[0778]¹H-NMR (CDCl₃) δ: 1.65-1.70 (2H, m), 1.98-2.06 (2H, m), 2.27-2.70(9H, m), 3.46 (2H, s), 5.30 (2H, brs), 5.74 (1H, brs), 6.04 (1H, brs),6.09 (1H, t), 6.79 (1H, d), 7.02 (1H, dd), 7.18-7.41 (6H, m), 7.54 (1H,dd), 8.43 (1H, dd).

[0779] MS m/z: 504 (M+1)

EXAMPLE 288

[0780]4-(4-Chlorophenyl)-1-[3-(7-(2-ethoxycarboxy)ethyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0781] The titled compound was prepared by following the procedure ofexample 165, but replacing the product of example 164 with the productof example 310.

[0782]¹H-NMR (CDCl₃) δ: 1.23 (3H, t), 1.63-1.71 (3H, m), 1.98-2.10 (2H,m), 2.35-2.71 (10H, m), 2.89 (2H, t), 4.13 (2H, q), 5.31 (2H, brs), 6.08(1H, t), 6.78 (1H, d), 7.00 (1H, dd), 7.12 (1H, d), 7.26-7.44 (5H, m),7.57 (1H, dd), 8.49 (1H, dd).

[0783] MS m/z: 548 (M+1)

EXAMPLE 289

[0784]4-(4-Chlorophenyl)-1-[3-(7-(1-(3-hydroxy)propyl)-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0785] The titled compound was prepared by following the procedure ofexample 133, but replacing the product of example 48 with the product ofexample 288. 1

[0786]¹H-NMR (DMSO-d₆) δ: 1.45-1.50 (2H, m), 1.66-1.80 (4H, m),2.26-2.57 (10H, m), 3.41 (2H, q), 4.46 (1H, t), 4.83 (1H, s), 5.23 (2H,brs), 6.14 (1H, t), 6.71 (1H, d), 7.01 (1H, dd), 7.13 (1H, d), 7.34-7.48(5H, m), 7.72 (1H, dd), 8.49 (1H, dd).

[0787] MS m/z: 505 (M+1)

EXAMPLE 290

[0788]4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2,3-dihydroxy)propyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0789] To a solution of product of example 170 (6.9 g) intetrahydrofuran (70 ml) and water (14 ml) were added N-methylmorpholineoxide(1.7 g) and osmium tetraoxide at 0° C., and the mixture was stirredat room temperature for 3 hours. Ethyl acetate was added to the mixture,the aqueous layer was separated. Chloroform-isopropanol (4:1) was addedto the aqueous layer, the organic layer was extracted, and dried withmagnesium sulfate. The solvent was distilled off under reduced pressureto give the titled compound (7.0 g).

[0790]¹H-NMR (CDCl₃) δ: 1.65-1.73 (2H, m), 1.95-2.10 (2H, m), 2.30-2.75(13H, m), 3.45-3.50 (1H, m), 3.60-3.65 (1H, m), 3.83-3.90 (1H, m), 5.28(2H, brs), 6.06 (1H, t), 6.84 (1H, d), 7.03 (1H, dd), 7.15 (1H, d),7.26-7.43 (5H, m), 7.57 (1H, dd), 8.49 (1H, dd).

[0791] MS m/z: 521 (M+1)

EXAMPLE 292

[0792]4-(4-Chlorophenyl)-1-[3-(7-(2-furyl)-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0793] The titled compound was prepared by following the procedure ofexample 170, but replacing allyltributyltin with ethyl(2-furyl)tributyltin.

[0794]¹H-NMR (CDCl₃) δ: 1.70-1.80 (3H, m), 1.97-2.16 (2H, m), 2.3-2.8(8H, m), 5.36 (2H, m), 6.19 (1H, t), 6.45 (1H, dd), 6.55 (1H, d), 6.87(1H, d), 7.20-7.50 (7H, m), 7.60-7.65 (2H, m), 8.52 (1H, dd)

[0795] MS m/z: 513 (M+1)

EXAMPLE 2934-(4-Chlorophenyl)-1-[3-(7-ethoxycarbonylamino-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidine)propyl]piperidin-4-ol

[0796] A mixture of product of example 118 (490 mg) anddiphenylphosphonic azide (0.28 ml) was stirred at 1 10C for 30 minutes.After the mixture was cooled, and triethylamine (0.14 ml) and ethanol (5ml) were added, and the mixture was heated to reflux for 8 hours. Thereaction mixture was diluted with ethyl acetate and filterd throughCelite. The filtrate was washed with saturated aqueous sodiumbicarbonate, and dried over magnesium sulfate. The solvent was removedunder reduced pressure and the residue was purified by silica gel columnchromatography (chloroform:methanol=10: 1) to give the titled compound(210 mg).

[0797]¹H-NMR (CDCl₃) δ: 1.31 (3H, t), 1.65-1.70 (2H, m), 2.01-2.09 (2H,m), 2.36-2.70 (8H, m), 4.21 (2H, q), 5.30 (2H, brs), 6.13 (1H, t), 6.46(1H, brs), 6.80 (1H, d), 7.02 (1H, dd), 7.28-7.50 (6H, m), 7.57 (1H,dd), 8.50 (1H, dd).

[0798] MS m/z: 534 (M+H)

EXAMPLE 294

[0799]1-[Bis(ethoxycarbonylmetyl)methoxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol

[0800] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with diethyl bromomalonate.

[0801]¹H-NMR (CDCl₃) δ: 1.30 (3H, t), 1.66-1.71 (2H, m), 1.98-2.09 (2H,m), 2.35-2.69 (9H, m), 4.30 (2H, q), 5.14 (1H, s), 5.26 (2H, brs), 6.10(1H, t), 6.78 (2H, d), 7.00 (1H, t), 7.26-7.45 (5H, m), 7.57 (1H, dd),8.43 (1H, dd).

[0802] MS m/z: 621 (M+1)

EXAMPLE 295

[0803]1-[1,1-Bis(ethoxycarbonylmetyl)ethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol

[0804] The titled compound was prepared by following the procedure ofexample 46, but replacing ethyl iodide with diethyl2-bromo-2-methylmalonate.

[0805]¹H-NMR (CDCl₃) δ: 1.27 (6H, t), 1.65-1.70 (5H, m), 1.99-2.08 (3H,m), 2.31-2.69 (8H, m), 4.28 (4H, q), 5.27 (2H, brs), 6.06 (1H, t), 6.72(1H, d), 6.80 (1H, dd), 7.00 (1H, d), 7.27-7.45 (5H, m), 7.56 (1H, dd),8.46 (1H, dd).

EXAMPLE 296

[0806]4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(2-hydroxy-1-hydroxymethyl)ethyloxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0807] The titled compound was prepared by following the procedure ofexample 199, but replacing the product of example 138 with the productof example 294.

[0808]¹H-NMR (CDCl₃) δ: 1.70-1.75 (2H, m), 2.10-2.80 (1H, m), 3.90 (4H,d), 4.36 (1H, quint), 5.28 (2H, brs), 6.13 (1H, t), 6.71-6.87 (2H, m),7.00 (1H, d), 7.29-7.45 (5H, m), 7.58 (1H, dd), 8.51 (1H, dd).

[0809] MS m/z: 537 (M+1)

EXAMPLE 297

[0810]1-[1,1-Bis(hydroxymetyl)ethyloxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)-piperidin-4-ol

[0811] The titled compound was prepared by following the procedure ofexample 199, but replacing the product of example 138 with the productof example 295.

[0812]¹H-NMR (CDCl₃) δ: 1.09 (3H, s), 1.66-1.71 (2H, m), 1.90-2.10 (3H,m), 2.37-2.75 (8H, m), 3.72-3.82 (4H, m), 5.29 (2H, brs), 6.05 (1H, t),6.77 (1H, d), 6.88 (1H, dd), 7.03 (1H, d), 7.26-7.43 (5H, m), 7.56 (1H,dd), 8.48 (1H, dd).

[0813] MS m/z: 551 (M+1)

EXAMPLE 305

[0814]1-[3-(5,11-dihydro-7-(2-hydroxyethyl)aminocarbonyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]-4-(4-chlorophenyl)piperidin-4-ol

[0815] The titled compound was prepared by following the procedure ofexample 198, but replacing dimethylamine hydrochloride with2-hydroxyehylamine.

[0816]¹H-NMR (CDCl₃) δ: 1.65-1.70 (2H, m), 2.03-2.06 (2H, m), 2.21 (1H,d), 2.32-2.68 (8H, m), 3.63 (2H, dt), 3.83 (2H, t), 5.37 (2H, brs), 6.18(1H, t), 6.67 (1H, brs), 7.25-7.54 (7H, m), 7.86 (1H, dd), 8,50 (1H,dd).

[0817] MS m/z: 534 (M+1)

EXAMPLE 306

[0818]4-(4-Chlorophenyl)-1-[3-(5,11-dihydro-7-(1-cyclohexyloxycarbonyloxy)ethyloxycarbonyl[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-oldihydrochloride

[0819] To a solution of product of example 118 (1. 1 g) indimethylformamide (15 ml) were added sodium iodide(0.17 g), potassiumcarbonate (0.38 g) and cyclohexyl 1-chloroethyl carbonate (J.Antibiotics, 1987, 40, 81.) (0.57 g) at room temperature. The mixturewas stirred at 70° C. for 1 hour. Water and ethyl acetate were added tothe reaction mixture, the organic layer was separated and washed withsaturated aqueous sodium chloride, and dried with magnesium sulfate. Thesolvent was distilled off under reduced pressure and the residue waspurified by silica gel column chromatography (ethyl acetate:methanol=100:3). The obtained oil was dissolved with ethyl acetate, and4 N hydrochloric acid ethyl acetate solution (0.8 ml) was added. Theprecipitation was filtered to give the titled compound (0.96 g).

[0820]¹H-NMR (DMSO-d₆) δ: 1.22-1.47 (6H, m), 1.58 (3H, d), 1.63-1.81(6H, m), 2.38-3.30 (10H, m), 4.07-4.59 (1H, m), 5.80 (2H, brs), 6.28(1H, t), 6.87 (1H, q), 6.97 (1H, d), 7.40-7.49 (4H, m), 7.64 (1H, dd),7.79 (1H, dd), 7.96 (1H, d), 8.03 (1H, dd), 8.65 (1H, dd), 11.07 (1H,brs).

[0821] MS m/z: 661[(M−2HCl)+1]

EXAMPLE 310

[0822]4-(4-Chlorophenyl)-1-[3-(7-(2-ethoxycarboxy)ethenyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0823] The titled compound was prepared by following the procedure ofexample 171, but replacing t-butyl acrylate with ethyl acrylate.

[0824]¹H-NMR (CDCl₃) δ: 1.33 (3H, t), 1.63-1.71 (3H, m), 1.98-2.10 (2H,m), 2.35-2.72 (8H, m), 4.25 (2H, q), 5.36 (2H, brs), 6.10 (1H, t), 6.33(1H, d), 6.85 (1H, d), 7.22-7.44 (7H, m), 7.58-7.65 (2H, m), 8.53 (1H,dd).

EXAMPLE 311

[0825]4-(4-Chlorophenyl)-1-[3-(7-(1-(2-ethyl-2-hydroxy)butyl)oxy-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0826] The titled compound was prepared by following the procedure ofexample 200, but replacing ethylmagnesium bromide with methylmagnesiumbromide.

[0827]¹H-NMR (CDCl₃) δ: 0.93 (6H, t), 1.60-1.70 (6H, m), 1.95-2.10 (3H,m), 2.36-2.70 (8H, m), 3.79 (2H, s), 5.28 (2H, brs), 6.09 (1H, t),6.77-6.86 (3H, m), 7.24-7.43 (5H, m), 7.57 (1H, dd), 8.47 (1H, dd).

[0828] MS m/z: 563 (M+I)

EXAMPLE 312

[0829]4-(4-Chlorophenyl)-1-[3-(7-(2-(2,3-dimethyl-3-hydroxy)butyl)oxy-5,11-dihydro[1]benzoxepino [2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0830] The titled compound was prepared by following the procedure ofexample 200, but replacing the product of example 48 with the product ofexample 138.

[0831]¹H-NMR (CDCl₃) δ: 1.22 (6H, s), 1.32 (6H, s), 1.66-1.71 (2H, m),1.99-2.10 (2H, m), 2.35-2.85 (9H, m), 3.77 (2H, s), 5.28 (2H, brs), 6.04(1H, t), 6.74-6.89 (3H, m), 7.26-7.43 (5H, m), 7.57 (1H, dd), 8.44 (1H,dd).

[0832] MS m/z: 563 (M+I)

EXAMPLE 314

[0833]4-(4-Chlorophenyl)-1-[3-(7-formyl-5,11-dihydro[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]piperidin-4-ol

[0834] To a solution of the product of example 274 (1.0 g) in methylenechloride(200 ml) was added manganese(IV) oxide(3.0 g), and thesuspension was stirred at ambient temperature for 12 hours. The reactionmixture was diluted with ethyl acetate and filtered through Celite. Thesolvent was evaporated under reduced pressure to give the titledcompound(930 mg).

[0835]¹H-NMR (CDCl₃) δ: 1.71-1.80 (3H, m), 1.98-2.09 (2H, m), 2.35-2.43(4H, m), 2.53-2.69 (4H, m), 5.30 (2H, brs), 6.24 (1H, t), 6.95 (1H, d),7.27-7.44 (5H, m), 7.61 (1H, dd), 7.67 (1H, dd), 7.85 (1H, d), 8.54 (1H,dd), 9.88 (1H, s).

EXAMPLE 316

[0836] To a stirred solution of phenol containing the product of Example44 (1.0 mmol) and K₂CO₃ (1.5 mmol) in THF (10 mL) at RT was addedN,N-dimethylcarbamoylchloride (1.2 mmol). The reaction was stirred atreflux for 24 hrs. Excess solvent was removed and pure compound wasisolated via silica gel chromatography eluting with 5% MeOH/CH₂Cl₂. MSm/z: (M+535)

EXAMPLE 317

[0837] To a stirred solution of phenol containing the product of Example44 (1.0 mmol) and K₂CO₃ (1.5 mmol) in THF (10 mL) at RT was addedmorpholinocarbamoylchloride (1.2 mmol). The reaction was stirred atreflux for 24 hrs. Excess solvent was removed and pure compound wasisolated via silica gel chromatography eluting with 5% MeOH/CH₂Cl₂. MSm/z: (M+577)

EXAMPLE 318

[0838] To a stirred solution of phenol containing the product of Example44 (1.0 mmol) in DMF at RT was added NaH (1.5 mmol) followed by theaddition of N-isopropylisocyanate (1.5 mmol). The reaction was heated to60° C. for 6 hrs. The reaction was quenched with 1.5 equivalents of H₂Oand excess DMF was removed under reduced pressure. Residue was chargedon a silica gel column and eluted off with 5% MeOH/CH₂Cl₂. MS m/z:(M+548)

EXAMPLE 319

[0839] To a stirred solution of phenol containing the product of Example44 (1.0 mmol) and K₂CO₃ (1.5 mmol) in THF (10 mL) at RT was addedN-methyl-N-phenylcarbamoylchloride (1.2 mmol). The reaction was stirredat reflux for 24 hrs. Excess solvent was removed and pure compound wasisolated via silica gel chromatography eluting with 5% MeOH/CH₂Cl₂. MSm/z: (M+597)

EXAMPLE 320

[0840] To a stirred solution of phenol containing the product of Example44 (1.0 mmol) in DMF at RT was added NaH (1.5 mmol) followed by theaddition of N-phenylisocyanate (1.5 mmol). The reaction was heated to60° C. for 6 hrs. The reaction was quenched with 1.5 equivalents of H₂Oand excess DMF was removed under reduced pressure. Residue was chargedon a silica gel column and eluted off with 5% MeOH/CH₂Cl₂. MS m/z:(M+583)

EXAMPLE 321

[0841] To a stirred solution of phenol containing the product of Example44 (1.0 mmol) in DMF at RT was added NaH (1.5 mmol) followed by theaddition of N-(3-pyridyl)isocyanate(1.5 mmol). The reaction was heatedto 60° C. for 6 hrs. The reaction was quenched with 1.5 equivalents ofH₂O and excess DMF was removed under reduced pressure. Residue wascharged on a silica gel column and eluted off with 5% MeOH/CH₂Cl₂. MSm/z: (M+584)

EXAMPLE 322

[0842] To a stirred solution of phenol containing the product of Example44 (1.0 mmol) and K₂CO₃ (1.5 mmol) in THF (10 mL) at RT was addedpyrolidinylcarbamoylchloride (1.2 mmol). The reaction was stirred atreflux for 24 hrs. Excess solvent was removed and pure compound wasisolated via silica gel chromatography eluting with 5% MeOH/CH₂Cl₂. MSm/z: (M+560)

EXAMPLE 323

[0843] The compound was prepared by following the procedure for example45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with4-(4-chlorophenyl)-4-cyanopiperidine. MS m/z: (M+486).

EXAMPLE 324

[0844] To a cold (0° C.) stirred solution of Example 323 (0.50 g, 0.104mmol) in anhydrous THF (5 mL) was added lithium aluminum hydride (8 mg,0.21 mmol). The reaction was stirred at RT for 2 hrs. The reaction wasthen quenched by the careful addition of H₂O (0.21 mL), 15% aqueous KOH(0.21 mL), then H₂O (0.21 mL). The organic layer was separated and driedover Na₂SO₄. The compound was purified via silica gel flashchromatography eluting with 10% methanol/methylene chloride. MS m/z:(M+490).

EXAMPLE 325

[0845] The compound can be obtained by the reduction of the azidofunctionality of Example 187 with a reducing agent, such as triphenylphoshine, lithium aluminum hydride, sodium borohydride, in a solventsuch as tetrahydrofuran or diethyl ether in reaction temperature rangesfrom 0° C. to reflux with a reaction time between 5 minutes and 72hours.

EXAMPLE 326

[0846] The compound was prepared by following the procedure for example45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with4-(4-chlorophenyl)-4-methylpiperidine provide in Example 329, steps 1-3.MS m/z: (M+475)

EXAMPLE 328

[0847] Step 1

[0848] N-benzyl-4-(4-chlorophenyl)-4-hydroxypiperidine: FIG. 8a

[0849] To a stirred solution of commercially available4-(4-chlorophenyl)-4-hydroxypiperidine (10 g, 47 mmol., 1) in anhydrousDMF (10 mL) was added benzyl bromide (5.6 mL, 47 mmol) and K₂CO₃ (7.4 g,94 mmol.) and stirred at RT overnight. Excess solvent was removed underreduced pressure, brought up into CH₂Cl₂ (100 mL) washed with H₂O (2×50mL). Organic layer separated, dried over Na₂SO₄ and charged on a silicagel flash column. Eluting off with 2% MeOH/CH₂Cl₂ 10 g 2 (80% yield) wasobtained as a viscous liquid. MS m/z: (M+303)

[0850] Step 2

[0851] N-benzyl-4-(4-chlorophenyl)-4-fluoropiperidine: FIG. 8a

[0852] To a cold (-78° C.) solution of 2 (10 g, 33 mmol) in CH₂Cl₂ (20mL) was slowly added DAST (diethylaminosulfur trifluoride, 5.3 mL, 39.8mmol) under an inert atmosphere. The reaction was stirred at −78° C. foran additional 45 min. The reaction was quenched at −78° C. by the slowaddition of enough saturated aqueous sodium bicarbonate solution toafford a pH>8. This reaction resulted a quantitative conversion of thestarting material to a 1:1 mixture of fluoropiperidine 3 and4-(4-chlorophenyl)tetrahydropyridine 4. The mixture of 3 and 4 (3.5 g,mixture, ˜35% yield) was purified via silica gel flash chromatography,eluting with 2% MeOH/CH₂Cl₂. This mixture proved to be inseparable bysilica gel flash chromatography. In order to separate out the desiredproduct, the mixture of 3 and 4 were subjected to osmium tetroxideoxidation.

[0853] To a stirred solution of the mixture of 3 and 4 (1.8 g) inacetone/H₂O (5: 1, 10 mL) was added a catalytic amount of OSO₄ inisopropanol (2.5 mol %, 1 mL) and N-methylmorpholine-N-oxide (0.69 g,6.56 mmol). The reaction was stirred at RT overnight. The reaction wasthen evaporated to dryness, brought up into CH₂Cl₂ and washed withNaHSO3. This reaction resulted in the dihydroxylation of the undesired 4to 5 and the clean separation of the desired fluoropiperidine 3 (1.0 g,55% yield) from the byproduct by silica gel flash chromatography elutingwith 2% MeOH/CH₂Cl₂. MS

[0854] m/z: (M+306)

[0855] Step 3

[0856] 4-(4-chlorophenyl)-4-fluoropiperidine: FIG. 8a

[0857] To a cold (0° C.) solution of 3 (1.07 g, 3.5 mmol) in1,2-dichloroethane was added 1,1-chloroethylchloroformate (0.45 mL, 4.2mmol). The reaction was then heated to reflux for 2 hrs. Excess solventwas removed and the residue was brought up into 5 mL methanol. Themixture was refluxed for 2 hrs and excess methanol was removed underreduced pressure. Precipitation of the hydrochloride salt of 6 by theaddition of CH₂Cl₂/hexane (1:1) followed by filtration resulted in thequantitative isolation of the desired crystalline product 6 (80%, 0.70g). MS m/z: (M+215)

[0858] Step 4

[0859] The compound was prepared by following the procedure for example44, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with4-(4-chlorophenyl)-4-fluoropiperidine.

[0860] MS m/z: (M+466)

EXAMPLE 329

[0861] Step 1

[0862] N-benzyl-4-methylpiperidine: FIG. 8c

[0863] To a cold (-78° C.) stirred solution of 1.4 M methyllithium inTHF (39 mL, 54 mmol) under an inert atmosphere was addedN-benzyl-4-oxopiperidine (1, 5.1 g, 27 mmol). The reaction was stirredat −78° C. for 2 hrs. The reaction was quenched by the slow addition ofsaturated aqueous NH₄Cl, the organic layer was separated and dried overNa₂SO₄. Pure methylpiperidine (2) was isolated via silica gel flashchromatography eluting with 5% MeOH/CH₂Cl₂. MS m/z: (M+206)

[0864] Step 2

[0865] N-benzyl-4-(4-chlorophenyl)-4-methylpiperidine: FIG. 8c

[0866] To a flask containing chlorobenzene (10 mL, excess) andmethylpiperidine (0.42 g, 2.06 mmol, 2) was added aluminum trichloride(1.65 mL, 12.4 mmol). The reaction was heated to reflux for 24 hrs.Excess chlorobenzene was removed under reduced pressure and pure 3 wasobtained via silica gel flash chromatography eluting with %

[0867] EtOAc/hexane. MS m/z: (M+300)

[0868] Step 3

[0869] 4-(4-chlorophenyl)-4-methylpiperidine: FIG. 8c

[0870] To a cold (0° C.) solution ofN-benzyl-4-(4-chlorophenyl)-4-methylpiperidine (3) (0.41 g, 1.4 mmol) inCH₂Cl₂ was 1.1 equivalent of 1-chloroethylchloroformate. The reactionwas then heated to reflux for 2 hrs. Excess solvent was removed and theresidue was brought up into methanol. The mixture was refluxed for 2 hrsand excess methanol was removed under reduced pressure. Precipitation ofthe hydrochloride salt 4 by the addition of CH₂Cl₂ followed byfiltration resulted in the quantitative isolation of the desiredcrystalline product 4 (100%, 0.34 g). MS m/z: (M+210)

[0871] Step 4

[0872] The compound was prepared by following the procedure for example44, step 2, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with4-(4-chlorophenyl)-4-methylpiperidine. MS m/z: (M+461)

EXAMPLE 330

[0873] The compound was prepared by following the procedure for example199, but replacing the resultant compound of example 44 with theresultant compound of Example 329. MS m/z: (M+533)

EXAMPLE 331

[0874] Step 1

[0875] A mixture of epichlorohydrin (5.92 g, 64 mmol) andbenzhydrylamine (11.7 g, 64 mmol) in MeOH (120 mL) was stirred under theprotection of argon at room temperature for 48 hours. The mixture wasthen stirred at 50° C. for 72 hours. The reaction mixture was thenstirred at room temperature for 72 hours. The reaction mixture wasconcentrated in vacuo and partitioned between EtOAc and H₂O. The aqueouslayer was extracted with EtOAc (200 mL×3), dried over MgSO₄ andconcentrated in vacuo. Chromatographic purification on silica gel(CH₂Cl₂/MeOH =95/5) provided 10.0 g (65%) of1-benzhydril-3-hydroxyazetidine. m/z 240 (m+1)

[0876] Step 2

[0877] A mixture 1-benzhydril-3-hydroxyazetidine (2.6 g, 11 mmol) andpalladium hydroxide on active carbon (0.26 g, w/w 20%) in EtOH (40 mL)was shaken in hydrogenation parr under 60 psi for 24 hours. The reactionmixture was filtered through celite and concentrated under vacuum.Concentration in vacuo provided 0.75 (95%) 3-hydroxyazetidine. ¹H NMR(250 MHz, CD₃OD) 3.81-3.92 (2H, m), 4.14-4.25 (2H, m), 4.61-4.69 (1H,m).

[0878] Step 3

[0879] The compound1-[3-(5,11-dihydro-7-(methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]azetidin-3-olwas prepared by following the procedure for example 45, step 3, butreplacing 4-(4-chlorophenyl)-4-hydroxypiperidine with3-hydroxyazetidine. m/z 339 (m+1).

[0880] Step 4

[0881] To a mixture of morpholine N-oxide (0.028 g, 0.244 mmol), crushedmolecular sieves (0.066 g) and Pr₄N+RO₄ (0.01 g, 0.024 mmol) in CH₂Cl₂was added the1-[3-(5,11-dihydro-7-(methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]azetidin-3-ol(0.055 g, 0.16 mmol) under the protection of argon. The mixture wasstirring over night at room temperature. The reaction mixture wasfiltered off through celite and concentrated under vacuum.Chromatographic purification on silica gel (CH₂Cl₂/MeOH =95/5 to 9/1)provided 0.033 g1-[3-(5,11-dihydro-7-(methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]azetidin-3-one(60%) of the desired product. m/z 337 (m+1)

[0882] Step 5

[0883] To a solution of1-[3-(5,11-dihydro-7-(methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]azetidin-3-one(0.06 g, 0.18 mmol) in THF (8 mL) was added dropwise a solution of4-chlorophenyl magnesium bromide in diethyl ether (1.0 M, 0.27 mL) underthe the protection of argon at 0° C. The reaction was stirred at roomtemperature for 1.5 hours and quenched by the addition of saturatedaqueous NH₄OH (4 mL). The aqueous layer was extracted with EtOAc (10mL×2), dried over MgSO4 and concentrated in vacuo. Chromatographicpurification on silica gel (CH₂Cl₂/MeOH=95/5) provided 0.048 g3-(4-chlorophenyl)-1-[3-(5,11-dihydro-7-(methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]azetidine(51%) m/z 449 (m+1)

EXAMPLE 332

[0884] Step 1

[0885] tert-Butyl 3-(4-chlorobenzoyl)-1-(2-aminoethyl) carbamate: FIG.10b

[0886] tert-Butyl N-(2-aminoethyl) carbamate (1, 0.50 g g, 3.12 mmol)was added to the mixture of 4-chlorobenzoic acid chloride (0.547 g, 3.12mmol) and Et₃N (1.74 mL, 12.5 mmol) in CH₂Cl₂ (20 mL) under theprotection of argon. Stirring at room temperature for 2 hours. Thereaction mixture was diluted with H₂O (25 mL), extracted with CH₂Cl₂ (50mL×2), dried over MgSO₄ and concentrated in vacuo. Chromatographicpurification on silica gel (CH₂Cl₂/MeOH=95/5) to provide 0.86 g (2, 93%)of the desired product tert-Butyl 3-(4-chlorobenzoyl)-1-(2-aminoethyl)carbamate. MS m/z: (M+299).

[0887] Step 2

[0888] 1-(4-chlorobenzoyl)-1,2-ethylenediamine: FIG. 10b

[0889] Trifluoroacetic acid (7.5 mL) was added to the solution oftert-Butyl 3-(4-chlorobenzoyl)-1-(2-aminoethyl)carbamate (2, 0.86 g,2.89 mmol) in CH₂Cl₂ (35 mL) at 0° C. Stirring at room temperature for30 minutes. Concentration in vacuo provided 0.88 g (95%) of the desiredproduct 1-(4-chlorobenzoyl)-1,2-ethylenediamine (3). MS m/z: (M+199).

[0890] Step 3

[0891] The compound was prepared by following the procedure for example45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with1-(4-chlorobenzoyl)-1,3-propylenediamine. MS m/z: (M+465).

EXAMPLE 333

[0892] Step 1

[0893] 2-(4-Chlorophenyl)-1-bromoethylene: FIG. 9c

[0894] To a solution of AlCl₃ (1.96 g, 14.7 mmol) in anhydrous CH₂Cl₂(50 mL), Borane-tert-butyl amine complex (2.57 g, 29.6 mmol) was addedat 0° C. under argon protection, stirred for 10 minutes and clearsolution was formed. 4-Chlorophenacyl bromide (1, 1.11 g, 4.91 mmol) inCH₂Cl₂ (5 mL) was added to the resulted mixture at 0° C. The reactionwas stirred for 1.5 hours and then quenched by the addition of 0.1 N HCl(25 mL). The mixture was extracted with EtOAc (80 mL×3), dried overMgSO4 and concentrated in vacuo. Chromatographic purification on silicagel (Hexane/EtOAc=9:1) provided 0.85 g (84%) of2-(4-chlorophenyl)-1-bromoethylene (2). MS m/z: (M+219).

[0895] Step 2

[0896] 2-(4-chlorophenyl)-1-(N-methyl)ethylamine: FIG. 9c

[0897] A mixture of 2-(4-chlorophenyl)-1-bromoethylene (2, 1.02 g, 4.62mmol), EtOH (3 mL) and H₂NMe in H₂O (6 mL, 40% w/w) was heated at 135 0°C. over night. The mixture was cooled down to room temperature. Themixture was extracted with Et₂O (5 mL×2), dried over MgSO₄ andconcentrated in vacuo. Chromatographic purification on silica gel(CH₂Cl₂/MeOH/NH₄OH=9/1/0.1) provided 0.61 g2-(4-chlorophenyl)-1-(N-methyl)ethylamine (3, 79%). MS m/z: (M+170).

[0898] Step 3

[0899] The compound was prepared by following the procedure for example45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with2-(4-chlorophenyl)-1-(N-methyl)ethylamine. MS m/z: (M+451).

EXAMPLE 334

[0900] Step 1

[0901] 3-(4-chlorophenyl)-1-N-methylaminopropane: FIG. 9e

[0902] A mixture of 3-(4-chlorophenyl)-1-bromoropane (1, 0.70 g, 3.73mmol), EtOH (3 mL) and H₂NMe in H₂O (6 mL, 40% w/w) was heated at 135 0Covernight. The mixture was then cooled down to room temperature. Themixture was extracted with Et₂O (5 mL×2), dried over MgSO₄ andconcentrated in vacuo. Chromatographic purification on silica gel(CH₂Cl₂/MeOH/NH₄OH=9/1/0.1) provided 0.5 g (76%) of3-(4-chlorophenyl)-1-N-methylaminopropane (2). MS m/z: (M+189).

[0903] Step 2

[0904] The compound was prepared by following the procedure for example45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with3-(4-chlorophenyl)-1-N-methylaminopropane. MS m/z: (M+450).

EXAMPLE 335

[0905] Step 1

[0906] 3-(4-chlorophenyl)-3-chloro-1-hydroxypropane: FIG. 9d

[0907] To 3,4′-Dichloropropylphenone (0.52 g, 2.53 mmol) in anhydrousMeOH (10 mL) at 0° C. under the protection of argon, NaBH₄ (0.23 g, 3.03mmol) was added to the solution by several portions. The reaction wasstirred under the same condition for 15 minutes. The mixture was warmedup to room temperature, stirred an additional 30 minutes, thenconcentration in vacuo. The residue was partitioned between EtOAc andH₂O. The aqueous layer was re-extracted with EtOAc (30 mL×2), dried overMgSO₄ and concentrated in vacuo. Chromatographic purification on silicagel (Hexane/EtOAc=(1/1) provided 0.52 g (99%) of3-(4-chlorophenyl)-3-chloro-1-hydroxypropane. MS m/z: (M+205).

[0908] Step 2

[0909] The compound was prepared by following the procedure for example45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with3-(4-chlorophenyl)-3-chloro-1-hydroxypropane. MS m/z: (M+481).

EXAMPLE 336

[0910] Step 1

[0911] 3-(4-chlorophenyl)-3-hydroxy-3-methyl-1-chloropropane: FIG. 10a

[0912] To 3,4′-Dichloropropylphenone (1, 1.10 g, 5.40 mmol) in anhydrousTHF at 0° C. under the protection of argon, was added MeMgBr (2.50 mL,7.35 mmol) dropwise at 0° C. The reaction was stirred at roomtemperature for an additional hour. The reaction was quenched by addingsaturated aqueous NH₄Cl. The reaction was then extracted with Et₂O (60mL×2), dried over MgSO₄ and concentrated in vacuo. Chromatographicpurification on silica gel (Hexane/EtOAc=10/1) provided 1.0 g (85%) of3-(4-chlorophenyl)-3-hydroxy-3-methyl-1-bromoropane (2). MS m/z:(M+219).

[0913] Step 2

[0914] 3-(4-chlorophenyl)-3-hydroxyl-3-methyl-1-N-methylaminopropane:FIG. 10a

[0915] A mixture of 3,3,3-(4-Chlorophenyl)-hydroxylmethyl-1-bromoropane(2, 1.04 g, 4.74 mmol), EtOH (5 mL) and H₂NMe in H₂O (10 mL, 40% w/w)was heated at 135 0° C. for 3 hours. The mixture was cooled down to roomtemperature. The mixture was extracted with Et₂O (5 mL×2), dried overMgSO₄ and concentrated in vauco. Chromatographic purification on silicagel (CH₂Cl₂/MeOH/NH₂OH=9/1/0.1) provided 1.01 g3-(4-chlorophenyl)-3-hydroxyl-3-methyl-1-N-methylaminopropane (3, 99%).MS m/z: (M+214).

[0916] Step 3

[0917] The compound was prepared by following the procedure for example45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with3-(4-chlorophenyl)-3-hydroxyl-3-methyl-1-N-methylaminopropane. MS m/z:(M+480).

EXAMPLE 345

[0918] Using the procedure of Example 45, but replacing5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with1-azaxanthone, gives the desired compound.

EXAMPLE 346

[0919] Using the procedure of Example 45, but replacing5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with1-4-azafluorene, gives the desired compound.

EXAMPLE 347

[0920] Using the procedure of Example 45, but replacing5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with7-amino-1-azaxanthone, gives the desired compound.

EXAMPLE 348

[0921] Using the procedure of Example 45, but replacing5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with4,5-diazafluorene, gives the desired compound.

EXAMPLE 349

[0922] Using the procedure of Example 45, but replacing5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridin-5-one with1-aza-7-nitroxanthone, gives the desired compound.

EXAMPLE 350

[0923]-3-(4-chlorophenyl)-1-[3-(5,11-dihydro-7-(methoxy[1]benzoxepino[2,3-b]pyridin-5-ylidene)propyl]pyrolidine

[0924] Step 1

[0925] A mixture of 1-benzyl-3-pyrrolidinone (10.0 g, 57 mmol),di-tert-butyl dicarbonate (13.7 g, 63 mmol) and palladium on activecarbon (2.5 g, w/w 20%) in MeOH was shaken in a Parr hydrogenationvessel (50 psi H₂) for 48 hours. The reaction mixture was filteredthrough celite and concentrated in vacuo. Chromatographic purificationon silica gel (Hexane/EtOAc=1/1) provided 6.21 g1-t-butoxycarbonyl-3-pyrrolidinone (59%). ¹H-NMR (250 MHz, CDCl₃) δ:1.46 (9H, s), 2.57 (2H, t, J=7.8 Hz), 3.71-3.75 (4H, m)

[0926] Step 2

[0927] To a stirred solution of 1-t-butoxycarbonyl-3-pyrrolidinone (0.57g, 3.23 mmol) in THF (10 mL) was added 4-chlorophenyl magnesium bromide(1.0 M, 5.2 mL) under the protection of argon at 0° C. The reaction wasstirred at room temperature for 1 hour then quenched by the addition ofsaturated aqueous NH₄OH (8 mL). The aqueous layer was extracted withEtOAc (50 mL×2), dried over MgSO₄ and concentrated in vacuo.Chromatographic purification on silica gel (Hexane/EtOAc=3/1) provided0.57 g 1-t-butoxycarbonyl-3-(4-chlorophenyl)-3-hydroxypyrolidine (60%).m/z 298 (m+1)

[0928] Step 3

[0929] To a stirred solution of1-t-butoxycarbonyl-3-(4-chlorophenyl)-3-hydroxypyrolidine (0.335 g, 1.28mmol) in CH₂Cl₂ (8 mL) was added trifluoroacetic acid (2 mL) at 0° C.slowly. The reaction was stirred at room temperature for 30 minutes andconcentrated in vacuo. This provided 0.355 g3-(4-chlorophenyl)-3-hydroxypyrolidine (100%) the desired product. m/z198 (m+1)

[0930] Step 4

[0931] The titled compound was prepared by following the procedure forexample 44 but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with3-(4-chlorophenyl)-3-hydroxypyrolidine. m/z 432 (m+1).

EXAMPLE 351

[0932] Step 1

[0933] 4-(4-chlorophenyl)-4-pyridine: FIG. 10d

[0934] To a solution of 4-bromopyridine (1, 1.94 g, mmol),4-chlorophenylboronic acid (2, 1.56 g, mmol) and K₂CO₃ (2.76 g, 2.0equiv) in ethanol/toluene (5 mL/100 mL) was added Pd(PPh₃)₃. Thereaction was refluxed for 1 hr, cooled back down to RT and quenched withH₂O (15 mL). The reaction mixture was extracted with EtOAc and theorganic layer was dried over Na₂SO₄. Pure 4-(4-chlorophenyl)-4-pyridine2 (1.3 g, 68% yield) was isolated after silica gel flash columnpurification eluting with 50% EtOAc/hexane. MS m/z: (M+191).

[0935] Step 2

[0936] The titled compound was prepared by following the procedure forexample 45, step 3, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidinewith 3-(4-chlorophenyl)-1-N-methylaminopropane. MS m/z: (M+456).

EXAMPLE 352

[0937] The compound was prepared by following the procedure for example44, but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with4-(4-chlorophenyl)-4-pyridine. MS m/z: (M+442).

EXAMPLE 353

[0938]5-(2-(N-(4-(4-Chlorophenyl)-4-hydroxycyclohexyl)-N-methyl)ethylidene)-5,11-dihydro-7-methoxy[1]benzoxepino[2,3-b]pyridine

[0939] The compound was prepared by the procedure of Example 57, step 3,but replacing 4-(4-chlorophenyl)-4-hydroxypiperidine with4-(4-N-methyl-(4-chlorophenyl)-4-hydroxycyclohexylamin. Theis startingmaterial can be prepared according to methods disclosed in Journal ofMedicinal Chemistry, Vol. 15, No. 12, pp.1239-1243 (1972).

[0940] Examples 4-7,9-11, 13-16, 20, 80-82, 84, 87-88, 92-110, 112-113,116, 119, 121, 124-127, 129, 136-137, 189, 193-195, 201, 202, 204,206-210, 213-214, 216-217, 233, 236, 238-241, 243-247, 250-251, 257-259,264-268, 270-272, 276-278, 282-287, 298-304, 305, 307-309, 313, 315, 327and 337-344 shown in FIGS. 6 and 11 can be prepared by the schemes setforth in FIGS. 1-5, 7, 8A-8C, 9A-9E, 10A-10 d and by the proceduresdescribed above.

[0941] Those skilled in the art will be able to recognize, or be able toascertain, using no more than routine experimentation, many equivalentsto the specific embodiments of the invention described herein. Suchequivalents are intended to be encompassed by the following claims.

What is claimed:
 1. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

and physiologically acceptable salts thereof, wherein: n is an integer from one to about four; M is >NR², >CR¹R², —O—CR¹R²—O— or —CH₂—CR¹R²—O—; The ring containing M is substituted or unsubstituted; q¹ is an integer, such as an integer from zero to about three; q² is an integer from zero to about one; R¹ is —H, —OH, —N₃, a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR³R⁴, —NR³R⁴ or R¹ is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M; R² is —H, —OH, an acyl group, a substituted acyl group, —NR⁵R⁶, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group); R³, R⁴, R⁵ and R⁶ are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R¹ and R², R³ and R⁴, or R⁵ and R⁶ taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring; Z is represented by:

wherein: X, is a bond, —O—, —S—, —CH₂—, —CH₂—CH₂—, —CH₂—S—, —S—CH₂—, —O—CH₂—, —CH₂—O—, —NR_(c)—CH₂—, —CH₂—NR_(c)—, —SO—CH₂—;CH₂—SO—, —S(O)₂—CH₂—, —CH₂—S(O)₂—, —CH═CH—, —NR_(c)—CO— or —CO—NR_(c)—; R_(c) is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.
 2. The method of claim 1 wherein R¹ is —H, —OH, —N₃, —CN, a halogen, a substituted aliphatic group, an aminoalkyl group —O-(aliphatic group), —O-(substituted aliphatic group), —NR³R⁴ or R¹ is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M; R² is —NR⁵R⁶, a substituted acyl group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, —O-(substituted or unsubstituted aromatic group); or R¹ and R² taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.
 3. The method of claim 1 wherein q¹ and q² are zero, and the compound is represented by the structural formula:


4. The method of claim 3 wherein M is >CR1R².
 5. The method of claim 1 wherein q¹ is one and q² is zero, and the compound is represented by the structural formula:


6. The method of claim 5 wherein M is >CR¹R².
 7. The method of claim 1 wherein q¹ is one and q² is two, and the compound is represented by the structural formula:


8. The method of claim 7 wherein M is >NR².
 9. The method of claim 1 wherein q¹ is one and q² is two, and the compound is represented by the structural formula:


10. The method of claim 9 wherein M is —O—CR¹R²—O— or —CH₂—CR¹R²—O—.
 11. The method of claim 9 wherein M is >NR² or >CR¹R²; and R¹ is a substituted aliphatic group or an aminoalkyl group.
 12. The method of claim 9 wherein M is >NR² or >CR¹R²; and R² is —O-(substituted or unsubstituted aromatic group).
 13. The method of claim 1 wherein Z is represented by the structural formula:

wherein: X, is —S—, —CH₂—, —CH₂—CH₂—, —CH₂—S—, —S—CH₂—, —O—CH₂—, —CH₂—O—, —NRC—CH₂—, —CH₂—NRC—, —SO—CH₂—, —CH₂—SO—, —S(O)₂—CH₂—, —CH₂—S(O)₂—, —CH═CH—, —NRC—CO—, a bond, —O—, or —CO—NRC—; R_(c) is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.
 14. The method of claim 13 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X₁ in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is —OH, —COOH, —NO₂, halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR²⁴R²⁵, —CONR²⁴R²⁵, Q-(aliphatic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O)_(u)—(CH₂)_(t)—C(O)OR²⁰, —(O)_(u)—(CH₂), —OC(O)R²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)O—R²⁰; R²⁰, R²¹ or R²² are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R²¹ and R²², taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring; Q is —NR²⁴C(O)— or —NR²⁴S(O)₂—; R²⁴ and R²⁵ are independently —H, —OH, an aliphatic group or a substituted aliphatic group; u is zero or one; and t is an integer from zero to about
 3. 15. The method of claim 14 wherein R⁴⁰ is represented by —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²².
 16. The method of claim 15 wherein u is zero and t one to about three.
 17. The method of claim 15 wherein u is zero and t one to about three u is one and t is zero.
 18. The method of claim 15 wherein u and t are both zero.
 19. The method of claim 14 wherein R⁴⁰ is a aliphatic group that is substituted with —NR²⁴R²⁵ or —CONR²⁴R²⁵.
 20. The method of claim 14 wherein R⁴⁰ is —O-(aliphatic group) or —O-(substituted aliphatic group).
 21. The method of claim 14 wherein R⁴⁰ is —COOH.
 22. The method of claim 1 wherein X, is —CH₂—O—.
 23. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

and physiologically acceptable salts thereof, wherein: n is an integer from one to about four; M is >NR², >CR¹R², —O—CR¹R²—O— or —CH₂—CR¹R²—O—; The ring containing M is substituted or unsubstituted; R¹ is —H, —OH, —N₃, a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR³R⁴, —NR³R⁴ or R¹ is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M; R² is —H, —OH, an acyl group, a substituted acyl group, —NR⁵R⁶, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group); R³, R⁴, R⁵ and R⁶ are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R¹ and R², R³ and R⁴, or R⁵ and R⁶ taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring; Z is represented by:

wherein: X₁ is —S—, —CH₂—, —CH₂—CH₂—, —CH₂—S—, —S—CH₂—, —O—CH₂—, —CH₂—O—, —NR_(c)—CH₂—, —CH₂—NR_(c)—, —SO—CH₂—, —CH₂—SO—, —S(O)₂—CH₂—, —CH₂—S(O)₂—, —CH═CH—, —Nr_(c)—CO—, a bond, —O—, or —CO—NR_(c)—; R_(c) is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.
 24. The method of claim 23 wherein Z is represented by the structural formula:

wherein: X₁ is —S—, —CH₂—, —CH₂—CH₂—, —CH₂—S—, —S—CH₂—, —O—CH₂—, —CH₂—O—, —NR_(c)—CH₂—, —CH₂—NR_(c)—, —SO—CH₂—, —CH₂—SO—, —S(O)₂—CH₂—, —CH₂—S(O)₂—, —CH═CH—, —Nr_(c)—CO—, a bond, —O—, or —CO—NR_(c)—; R_(c) is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.
 25. The method of claim 24 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X₁ in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is —OH, —COOH, —NO₂, halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR²⁴R²⁵, —CONR²⁴R²⁵, Q-(aliphqtic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O)_(u)—(CH₂)_(t)—C(O)OR²⁰, —(O)_(u)—(CH₂)_(t)—OC(O)R²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)O—R²⁰; R²⁰, R²¹ or R²² are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R²¹ and R²², taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring; Q is —NR²⁴C(O)— or —NR²⁴S(O)₂—; R²⁴ and R²⁵ are independently —H, —OH, an aliphatic group or a substituted aliphatic group; u is zero or one; and t is an integer from zero to about
 3. 26. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

and physiologically acceptable salts thereof, wherein: n is an integer from one to about four; R⁵⁰ and R⁵¹ are each, independently, —H, R⁵⁰ and R⁵¹ are each independently —H, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —NR³R⁴, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, or a covalent bond between the nitrogen atom an adjacent carbon atom; R³ and R⁴ are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; Z is represented by:

wherein: X₁ is —S—, —CH₂—, —CH₂—CH₂—, —CH₂—S—, —S—CH₂—, —O—CH₂—, —CH₂—O—, —NR_(c)—CH₂—, —CH₂—NR_(c)—, —SO—CH₂—, —CH₂—SO—, —S(O)₂—CH₂—, —CH₂—S(O)₂—, —CH═CH—, —Nr_(c)—CO—, a bond, —O—, or —CO—NR_(c)—; R_(c) is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.
 27. The method of claim 26 wherein R⁵⁰ is a substituted aliphatic group; and R⁵¹ is —H, an aliphatic group or a substituted aliphatic group.
 28. The method of claim 27 wherein R⁵⁰ is a substituted aliphatic group bearing an aromatic substituent.
 29. The method of claim 27 wherein R⁵⁰ is a an aliphatic group which is substituted with a 4-chlorophenyl group.
 30. The method of claim 26 wherein Z is represented by the structural formula:

wherein: X₁ is —S—, —CH₂—, —CH₂—CH₂—, —CH₂—S—, —S—CH₂—, —O—CH₂—, —CH₂—O—, —NR_(c)—CH₂—, —CH₂—NR_(c)—, —SO—CH₂—, —CH₂—SO—, —S(O)₂—CH₂—, —CH₂—S(O)₂—, —CH═CH—, —Nr_(c)—CO—, a bond, —O—, or —CO—NR_(c)—; R_(c) is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.
 31. The method of claim 30 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X₁ in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is —OH, —COOH, —NO₂, halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR²⁴R²⁵, —CONR²⁴R²⁵, Q-(aliphqtic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O)_(u)—(CH₂)_(t)—C(O)OR², —(O)_(u)—(CH₂), —OC(O)R²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)O—R²⁰; R²⁰, R²¹ or R²² are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R²¹ and R²², taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring; Q is —NR²⁴C(O)— or —NR²⁴S(O)₂—; R²⁴ and R²⁵ are independently —H, —OH, an aliphatic group or a substituted aliphatic group; u is zero or one; and t is an integer from zero to about
 3. 32. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

or a physiologically acceptable salt thereof, wherein: M is CR1R²; R¹ is —OH; R² is 4-chlorophenyl; n is two; Z is represented by:

X₁ is —CH₂—O—; and R⁴⁰ is


33. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

or a physiologically acceptable salt thereof, wherein: M is CR¹R²; R¹ is —OH; R² is 4-chlorophenyl; n is two; Z is represented by:

X₁ is —CH₂—O—; and R⁴⁰ is —COOH.
 34. A method of treating a disease associated with aberrant leukocyte recruitment and/or activation, comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

or a physiologically acceptable salt thereof, wherein: M is CR¹R²; R¹ is —OH; R² is 4-chlorophenyl; n is two; Z is represented by:

X₁ is —CH₂—O—; and R⁴⁰ is


35. A compound represented by the following structural formula:

and physiologically acceptable salts thereof, wherein: n is an integer from one to about four; M is >NR², >CR¹R², —O—CR¹R²—O— or —CH₂—CR¹R²—O—; The ring containing M is substituted or unsubstituted; R¹ is —H, —OH, —N₃, a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR³R⁴, —NR³R⁴ or R¹ is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M; R² is —H, —OH, an acyl group, a substituted acyl group, —NR⁵R⁶, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group); R³, R⁴, R⁵ and R⁶ are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R¹ and R², R³ and R⁴, or R⁵ and R⁶ taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring; Z is represented by:

wherein: X, is —S—, —CH₂—, —CH₂—CH₂—, —CH₂—S—, —S—CH₂—, —O—CH₂—, —CH₂—O—, —NR_(c)—CH₂—, —CH₂—NR_(c)—, —SO—CH₂—, —CH₂—SO—, —S(O)₂—CH₂—, —CH₂—S(O)₂—, —CH═CH—, —NR_(c)—CO—, a bond, —O—, or —CO—NRC—; R_(c) is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.
 36. The compound of claim 35 wherein R¹ is —H, —OH, —N₃, —CN, a halogen, a substituted aliphatic group, an aminoalkyl group —O-(aliphatic group), —O-(substituted aliphatic group), —NR³R⁴ or R¹ is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M; R² is —NR⁵R⁶, a substituted acyl group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, —O-(substituted or unsubstituted aromatic group); or R¹and R² taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring.
 37. The compound of claim 35 wherein q¹ and q² are zero, and the compound is represented by the structural formula:


38. The compound of claim 37 wherein M is >CR¹R².
 39. The compound of claim 35 wherein q¹ is one and q² is zero, and the compound is represented by the structural formula:


40. The compound of claim 39 wherein M is >CR¹R².
 41. The compound of claim 35 wherein q¹ is one and q² is two, and the compound is represented by the structural formula:


42. The compound of claim 41 wherein M is >NR².
 43. The compound of claim 35 wherein q¹ is one and q² is two, and the compound is represented by the structural formula:


44. The compound of claim 43 wherein M is —O—CR¹R²—O— or —CH₂—CR¹R²—O—.
 45. The compound of claim 43 wherein M is >NR² or >CR¹R²; and R¹ is a substituted aliphatic group or an aminoalkyl group.
 46. The compound of claim 43 wherein M is >NR² or >CR¹R²; and R² is —O-(substituted or unsubstituted aromatic group).
 47. The compound of claim 35 wherein Z is represented by the structural formula:

wherein: X₁ is —S—, —CH₂—, —CH₂—CH₂—, —CH₂—S—, —S—CH₂—, —O—CH₂—, —CH₂—O—, —NR_(c)—CH₂—, —CH₂—NR_(c)—, —SO—CH₂—, —CH₂—SO—, —S(O)₂—CH₂—, —CH₂—S(O)₂—, —CH═CH—, —Nr_(c)—CO—, a bond, —O—, or —CO—NR_(c)—; R_(c) is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.
 48. The compound of claim 47 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X₁ in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is —OH, —COOH, —NO₂, halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR²⁴R²⁵, —CONR²⁴R²⁵, Q-(aliphqtic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O)_(u)—(CH₂)_(t)—C(O)OR²⁰, —(O)_(u)—(CH₂)_(t)—OC(O)R²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)O—R²⁰; R²⁰, R²¹ or R²² are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R²¹ and R²², taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring; Q is —NR²⁴C(O)— or —NR²⁴S(O)₂—; R²⁴ and R²⁵ are independently —H, —OH, an aliphatic group or a substituted aliphatic group; u is zero or one; and t is an integer from zero to about
 3. 49. The compound of claim 48 wherein R⁴⁰ is represented by —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²².
 50. The compound of claim 49 wherein u is zero and t one to about three.
 51. The compound of claim 49 wherein u is zero and t one to about three u is one and t is zero.
 52. The compound of claim 49 wherein u and t are both zero.
 53. The compound of claim 48 wherein R⁴⁰ is a aliphatic group that is substituted with —NR²⁴R²⁵ or —CONR²⁴R²⁵.
 54. The compound of claim 48 wherein R⁴⁰ is —O-(aliphatic group) or —O-(substituted aliphatic group).
 55. The compound of claim 48 wherein R⁴⁰ is —COOH.
 56. The compound of claim 35 wherein X₁ is —CH₂—O—.
 57. A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

and physiologically acceptable salts thereof, wherein: n is an integer from one to about four; M is >NR², >CR¹R², —O—CR¹R²—O— or —CH₂—CR¹R²—O—; The ring containing M is substituted or unsubstituted; R¹ is —H, —OH, —N₃, a halogen, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —O-(aliphatic group), —O-(substituted aliphatic group), —SH, —S-(aliphatic group), —S-(substituted aliphatic group), —OC(O)-(aliphatic group), —O—C(O)-(substituted aliphatic group), —C(O)O-(aliphatic group), —C(O)O-(substituted aliphatic group), —COOH, —CN, —CO—NR³R⁴, —NR³R⁴ or R¹ is a covalent bond between the ring atom at M and an adjacent carbon atom in the ring which contains M; R² is —H, —OH, an acyl group, a substituted acyl group, —NR⁵R⁶, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, —O-(substituted or unsubstituted aromatic group) or —O-(substituted or unsubstituted aliphatic group); R³, R⁴, R⁵ and R⁶ are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; or R¹and R², R³ and R⁴, or R⁵ and R⁶ taken together with the atom to which they are bonded, form a substituted or unsubstituted non-aromatic carbocyclic or heterocyclic ring; Z is represented by:

wherein R⁴⁰ is —OH, —COOH, —NO, halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR²⁴R²⁵, —CONR²⁴R²⁵, Q-(aliphqtic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O)_(u)—(CH₂)_(t)—C(O)OR²⁰, —(O)_(u)—(CH₂)_(t)—OC(O)R²¹, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)O—R²⁰; R²⁰, R²¹ or R²² are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R²¹ and R²², taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring; Q is —NR²⁴C(O)— or —NR²⁴S(O)₂—; R²⁴ and R²⁵ are independently —H, —OH, an aliphatic group or a substituted aliphatic group; u is zero or one; and t is an integer from zero to about
 3. 60. A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

and physiologically acceptable salts thereof, wherein: n is an integer from one to about four; R⁵⁰ and R⁵¹ are each, independently, —H, an aliphatic group, a substituted aliphatic group, an aminoalkyl group, —NR³R⁴, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group, a substituted non-aromatic heterocyclic group, or a covalent bond between the nitrogen atom an adjacent carbon atom; R³ and R⁴ are independently —H, an acyl group, a substituted acyl group, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group, a substituted benzyl group, a non-aromatic heterocyclic group or a substituted non-aromatic heterocyclic group; Z is represented by:

wherein: X₁ is —S—, —CH₂—, —CH₂—CH₂—, —CH₂—S—, —S—CH₂—, —O—CH₂—, —CH₂—O—, —NR_(c)—CH₂—, —CH₂—NR_(c)—, —SO—CH₂—, —CH₂—SO—, —S(O)₂—CH₂—, —CH₂—S(O)₂—, —CH═CH—, —Nr_(c)—CO—, a bond, —O—, or —CO—NR_(c)—; wherein: X₁ is —S—, —CH₂—, —CH₂—CH₂—, —CH₂—S—, —S—CH₂—, —O—CH₂—, —CH₂—O—, —NR_(c)—CH₂—, —CH₂—NR_(c)—, —SO—CH₂—, —CH₂—SO—, —S(O)₂—CH₂—, —CH₂—S(O)₂—, —CH═CH—, —NR_(c)—CO—, a bond, —O—, or —CO—NR_(c)—; R_(c) is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.
 58. The compound of claim 57 wherein Z is represented by the structural formula:

wherein: X₁ is —S—, —CH₂—, —CH₂—CH₂—, —CH₂—S—, —S—CH₂—, —O—CH₂—, —CH₂—O—, —NR_(c)—CH₂—, —CH₂—NR_(c)—, —SO—CH₂—, —CH₂—SO—, —S(O)₂—CH₂—, —CH₂—S(O)₂—, —CH═CH—, —NR_(c)—CO—, a bond, —O—, or —CO—NRC—; R_(c) is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.
 59. The compound of claim 58 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X, in ring C, and Z is represented by the structural formula: R_(c) is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.
 61. The compound of claim 60 wherein R⁵⁰ is a substituted aliphatic group; and R⁵⁰ is —H, an aliphatic group or a substituted aliphatic group.
 62. The compound of claim 61 wherein R⁵⁰ is a substituted aliphatic group bearing an aromatic substituent.
 63. The method of claim 61 wherein R⁵⁰ is a an aliphatic group that is substituted with a 4-chlorophenyl group.
 64. The compound of claim 60 wherein Z is represented by the structural formula:

wherein: X₁ is —S—, —CH₂—, —CH₂—CH₂—, —CH₂—S—, —S—CH₂—, —O—CH₂—, —CH₂—O—, —NR_(c)—CH₂—, —CH₂—NR_(c)—, —SO—CH₂—, —CH₂—SO—, —S(O)₂—CH₂—, —CH₂—S(O)₂—, —CH═CH—, —Nr_(c)—CO—, a bond, —O—, or —CO—NR_(c)—; R_(c) is —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group, a benzyl group or a substituted benzyl group; and Ring A and Ring B are independently substituted or unsubstituted.
 65. The compound of claim 64 wherein ring B is substituted para to the carbon atom of ring B that is bonded to X₁ in ring C, and Z is represented by the structural formula:

wherein R⁴⁰ is —OH, —COOH, —NO₂, halogen, aliphatic group, substituted aliphatic group, an aromatic group, a substituted aromatic group, —NR²⁴R²⁵, —CONR²⁴R²⁵, Q-(aliphqtic group), Q-(substituted aliphatic group), —O-(aliphatic group), —O-(substituted aliphatic group), —O-(aromatic group), —O-(substituted aromatic group), an electron withdrawing group, —(O)_(u)—(CH₂)_(t)—C(O)OR²”, —(O)_(u)—(CH₂)_(t)—OC(O)R²⁰, —(O)_(u)—(CH₂)_(t)—C(O)—NR²¹R²² or —(O)_(u)—(CH₂)_(t)—NHC(O)O—R²⁰; R²⁰, R²¹ or R²² are independently —H, an aliphatic group, a substituted aliphatic group, an aromatic group, a substituted aromatic group or a non-aromatic heterocyclic group; or R²¹ and R²², taken together with the nitrogen atom to which they are bonded, form a non-aromatic heterocyclic ring; Q is —NR²⁴C(O)— or —NR²⁴S(O)₂—; R²⁴ and R²⁵ are independently —H, —OH, an aliphatic group or a substituted aliphatic group; u is zero or one; and t is an integer from zero to about
 3. 66. A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

or a physiologically acceptable salt thereof, wherein: M is CR1R²; R¹ is —OH; R² is 4-chlorophenyl; n is two; Z is represented by:

X₁ is —CH₂—O—; and R⁴⁰ is


67. A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

or a physiologically acceptable salt thereof, wherein: M is CR¹R²; R¹ is —OH; R² is 4-chlorophenyl; n is two; Z is represented by:

X₁ is —CH₂—O—; and R⁴⁰ is —COOH.
 68. A compound of treating a disease associated with aberrant leukocyte recruitment and/or activation comprising administering to a subject in need thereof an effective amount of a compound represented by the following structural formula:

or a physiologically acceptable salt thereof, wherein: M is CR¹R²; R¹ is —OH; R² is 4-chlorophenyl; n is two; Z is represented by:

X₁ is —CH₂—O—; and R⁴⁰ is 